Imidazo[1,2-b]pyridazine derivatives as kinase inhibitors

ABSTRACT

The present invention is intended to provide a compound or a pharmacologically acceptable salt thereof which is useful in the treatment of a tumor through its ROS1 kinase enzyme activity inhibitory effect and NTRK kinase enzyme inhibitory effect. The present invention provides a compound having an imidazo[1,2-b]pyridazine structure represented by the general formula (I) or a pharmacologically acceptable salt thereof, and a pharmaceutical composition comprising the compound. In the formula, R 1 , G, T, Y 1 , Y 2 , Y 3 , and Y 4  are as defined herein.

TECHNICAL FIELD

The present invention relates to compounds having a particular chemicalstructure or pharmacologically acceptable salts thereof which have apotent inhibitory effect to ROS1 kinase and NTRK kinase.

BACKGROUND ART

The ROS1 gene encodes receptor tyrosine kinase discovered as a humanortholog of the cancer gene product v-ros of avian sarcoma virus UR2(University of Rochester tumor virus 2) (Non Patent Reference 1). TheROS1 fusion gene resulting from the chromosomal rearrangement containingthe ROS1 gene and the subsequent fusion of the ROS1 gene to another genewas discovered in a lioblastoma cell line U118MG. In the U118MG cells, agene encoding a Golgi protein FIG (fused in glioblastoma) is fused withthe ROS1 gene to form a gene encoding FIG-ROS1 fusion protein (NonPatent Reference 2). The fusion between FIG and ROS1 causes structuralchange that constitutively activates ROS1 kinase enzyme activity, andthe FIG-ROS1 fusion protein has cell transformation activity andtumorigenic activity mediated by the activation of the ROS1 signalingpathway involving STAT3, ERK, and SHP2 (Non Patent References 3 and 4).

The chromosomal translocation of the ROS1 gene has also been identifiedin a non-small cell lung cancer cell line HCC78 and clinical specimensof lung cancers. The fusion gene of the SLC34A2 gene and the ROS1 genehas been reported in the HCC78 cells, while the presence of thetransmembrane protein-encoding CD74-ROS1 fusion gene of the CD74 geneand the ROS1 gene has been reported in non-small cell lung cancerpatient specimens (Non Patent Reference 5). The fusion gene of the FIGgene and the ROS1 gene has been found in 2 out of 23 patient specimensof bile duct cancer (Non Patent Reference 6).

The large-scale screening of patient specimens using FISH (fluorescentin situ hybridization) has identified fusion genes of the ROS1 gene withSDC, CD74, EZR, SLC34A2, LRIG3, or TPM3. Any of the ROS1 fusion genesSDC-ROS1, CD74-ROS1, EZR-ROS1, SLC34A2-ROS1, LRIG3-ROS1, and TPM3-ROS1have been detected in 13 out of 1476 non small cell lung cancer patientspecimens (Non Patent Reference 7).

Likewise, the large-scale screening of non-small cell lung cancerpatient specimens using FISH has found the ROS1 fusion gene in 18 out of1073 cases (Non Patent Reference 8). In addition, analysis using patientspecimens has showed that the ROS1 gene is highly expressed in braintumor (Non Patent References 1 and 9).

ROS1 has been shown to be activated in cancer expressing the ROS1 fusiongene (e.g., non-small cell lung cancer, bile duct cancer, or braintumor) (Non Patent References 5 and 6). Thus, a drug that inhibits ROS1kinase activity can block the downstream of the ROS1 pathway, i.e.STAT3, ERK, SHP2, which contribute the tumor growth and tumor cellsurvival. Therefore, ROS1 is expected to be useful as a therapeutic drugfor cancer (Non Patent References 1, 6, and 8). Compounds such ascrizotinib (Non Patent Reference 8), TAE684 (Non Patent Reference 6),pyrazole derivatives (Non Patent References 10 and 11), andaminopyrazine derivatives (Patent Reference 1) have been reported tohave a ROS1 kinase enzyme activity inhibitory effect. These compounds,however, differ in structure from the compounds of the presentinvention.

Neurotrophic tyrosine kinase receptor, also called tropomyosin-relatedkinase (Trk), is a high-affinity receptor that is activated by a solublegrowth factor called neurotrophin (NT). The NTRK receptor family hasthree members: NTRK1 (also called TrkA), NTRK2 (also called TrkB), andNTRK3 (also called TrkC).

NT includes a plurality of proteins as follows: a nerve growth factor(NGF) which activates NTRK1, a brain-derived neurotrophic factor (BDNF)and NT-4/5 which activate NTRK2, and NT3 which activates NTRK3. EachNTRK receptor contains an extracellular domain (ligand-binding site), atransmembrane domain, and an intracellular domain (containing a kinasedomain). Upon binding to a ligand, each kinase catalyzesautophosphorylation and then activates the downstream signaltransduction pathway.

NTRK is widely expressed in nerve tissues during their developmentperiod and plays an important role for the maintenance and survival ofthese cells. The previous study shows that NTRK plays an important rolein both the development and function of the nervous system (Non PatentReference 12).

A large number of references state that NTRK signal transduction isassociated with cancer. For example, NTRK exists at a low expressionlevel in regions other than the nervous system in adult humans, whereasthe expression of NTRK is increased at the late stage of prostatecancer. In normal prostate tissues and androgen-dependent prostate tumorat the early state, NTRK1 is expressed only at a low level or anundetectable level, but neither NTRK2 nor NTRK3 is expressed. Inandrogen-independent prostate cancer at the late stage, however, allisoforms of the NTRK receptors and their ligands are overexpressed. Theevidence shows that these late-stage prostate cancer cells depend onNTRK for their tumor survival. Thus, NTRK inhibitors may induceapoptosis for androgen-independent prostate cancer (Non Patent Reference13). In addition, recent references also show that the overexpression,activation, amplification, fusion gene formation, or mutation of NTRK isrelated to neuroblastoma (Non Patent Reference 14), secretory breastcancer (Non Patent Reference 15), colorectal cancer (Non PatentReference 16), ovary cancer (Non Patent Reference 17), head and neckcancer (Non Patent Reference 18), pancreatic cancer (Non PatentReference 19), and melanoma (Non Patent Reference 20).

Selective NTRK tyrosine kinase inhibitors have been reported, includingCEP-751, CEP-701 (Non Patent Reference 21), indolocarbazole compounds(Patent Reference 2), oxindole compounds (Patent References 3 and 4),pyrazolyl condensed-ring compounds (Patent Reference 5), isothiazolecompounds (Non Patent Reference 22), and other various compounds (PatentReferences 6, 7, 8, 9, and 10). These compounds, however, differ instructure from the compound of the present invention.

Lck inhibitors (Patent Reference 11), PKC inhibitors (Patent References12 and 13), and NTRK inhibitors (Patent References 14 and 15) are knownas compounds having an imidazopyridazine skeleton. Nevertheless, none ofthe known compounds having an imidazopyridazine skeleton exhibit ROS1kinase enzyme inhibitory activity and NTRK inhibitory activity.

CITATION LIST Patent References

-   Patent Reference 1: WO2012/005299-   Patent Reference 2: WO01/14380-   Patent Reference 3: WO02/20479-   Patent Reference 4: WO02/20513-   Patent Reference 5: Japanese Patent Laid-Open No. 15-231687-   Patent Reference 6: WO2005/049033-   Patent Reference 7: WO2005/103010-   Patent Reference 8: WO2006/082392-   Patent Reference 9: WO2006/087530-   Patent Reference 10: WO2006/087538-   Patent Reference 11: WO2007/013673-   Patent Reference 12: WO2007/025540-   Patent Reference 13: WO2007/147646-   Patent Reference 14: WO2008/052734-   Patent Reference 15: WO2012/125667

Non Patent References

-   Non Patent Reference 1: Biochim. Biophys. Acta, 1795, 37-52 (2009)-   Non Patent Reference 2: Genes Chromosomes Cancer, 37, 58-71 (2003)-   Non Patent Reference 3: Proc. Natl. Acad. Sci. USA, 100, 916-921    (2003)-   Non Patent Reference 4: Cancer Res., 66, 7473-7481 (2006)-   Non Patent Reference 5: Cell, 131, 1190-1203 (2007)-   Non Patent Reference 6: PLoS One, 6 (1), e15640 (2011)-   Non Patent Reference 7: Nat. Medicine, 2658 (2012)-   Non Patent Reference 8: J. Clin. Oncol., 2011. 39. 4197 (2012)-   Non Patent Reference 9: Cancer Res., 69, 2180-2184 (2009)-   Non Patent Reference 10: Bioorg. Med. Chem. Lett., 19, 4720-4723    (2009)-   Non Patent Reference 11: Bioorg. Med. Chem. Lett., 19, 5622-5626    (2009)-   Non Patent Reference 12: Current Opinion in Neurobiology, 11,    272-280 (2001)-   Non Patent Reference 13: The Prostate, 45, 140-148 (2000)-   Non Patent Reference 14: Pediatr Blood Cancer, 59, 226-232 (2012)-   Non Patent Reference 15: Cancer Cell, 2, 367-376 (2002)-   Non Patent Reference 16: Science, 300, 949-949 (2003)-   Non Patent Reference 17: Clinical Cancer Research, 9, 2248-2259    (2003)-   Non Patent Reference 18: PLos ONE 7 (1), e30246 (2012)-   Non Patent Reference 21: Cancer Research, 59, 2395-2341 (1999)-   Non Patent Reference 22: Bioorg. Med. Chem. Lett., 16, 3444-3448    (2006)

SUMMARY OF INVENTION Technical Problem

An object of the present invention is to provide a novellow-molecular-weight compound that has a potent ROS1 kinase enzymeactivity inhibitory effect and NTRK kinase enzyme inhibitory activityand exhibits an antitumor effect.

Solution to Problem

The present invention relates to the following (1) to (47):

(1) A compound represented by the general formula (I) or apharmacologically acceptable salt thereof:

whereinR¹ represents a hydrogen atom, a C₁-C₆ alkyl group, a fluoro-C₁-C₆ alkylgroup, or a hydroxy-C₁-C₆ alkyl group;Q represents an oxygen atom or R^(a)N, whereinR^(a) represents a hydrogen atom or a C₁-C₆ alkyl group;G represents a phenyl group or a 5- or 6-membered heteroaryl grouphaving, in the ring, 1 to 3 heteroatoms independently selected from thegroup consisting of a nitrogen atom, an oxygen atom, and a sulfur atom,wherein the 5-membered heteroaryl group optionally has 1 or 2substituents independently selected from the group consisting of ahalogen atom, a cyano group, a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group,a dihalo-C₁-C₆ alkyl group, and a trihalo-C₁-C₆ alkyl group, andthe phenyl group and the 6-membered heteroaryl group each optionallyhave 1 to 3 substituents independently selected from the groupconsisting of a 5- or 6-membered heteroaryl group having, in the ring, 1to 3 heteroatoms independently selected from the group consisting of anitrogen atom, an oxygen atom, and a sulfur atom, a halogen atom, acyano group, a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, and atrihalo-C₁-C₆ alkyl group;T represents a nitrogen atom or CR^(b), whereinR^(b) represents a hydrogen atom, a halogen atom, a C₁-C₆ alkyl group, aC₁-C₆ alkoxy group, or a cyano group;Y¹ and Y² each independently represents a hydrogen atom, a halogen atom,a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, or a cyano group; andY³ and Y⁴ each independently represents a hydrogen atom,a group selected from group A described below, ora group represented by the following formula (II):

wherein

W represents an oxygen atom or CR^(c)R^(d), wherein

R^(c) and R^(d) each independently represents a hydrogen atom, a C₁-C₆alkyl group, or an amino group, or

R^(c) and R^(d) optionally form a C₃-C₆ cycloalkyl group together withthe carbon atom bonded to R^(c) and R^(d); n represents 0, 1, or 2;

R² and R³ each independently represents a hydrogen atom, an amino group,a C₁-C₆ alkyl group, an amino-C₁-C₆ alkyl group, a C₁-C₆ alkylaminogroup, or a di-C₁-C₆ alkylamino group

(provided that any one of Y³ and Y⁴ inevitably represents a hydrogenatom, and the other group represents a group other than a hydrogenatom),

group A: —O-M, —S-M, and —NH-M

(M represents a C₁-C₆ alkyl group having 1 or 2 substituentsindependently selected from group B described below, an amino-C₃-C₆cycloalkyl group, a 4- to 6-membered aliphatic heterocyclic group havingone nitrogen atom in the ring, or a 5- or 6-membered aliphaticheterocyclic group having 1 or 2 substituents independently selectedfrom group D described below and having one nitrogen atom in the ring),

group B: an amino group, a hydroxy group, a C₁-C₆ alkylamino group, adi-C₁-C₆ alkylamino group, a C₃-C₆ cycloalkylamino group, an amino-C₃-C₆cycloalkyl group, a hydroxy-C₁-C₆ alkylamino group, a 4- to 6-memberedaliphatic heterocyclic group having one nitrogen atom in the ring, and a6-membered aliphatic heterocyclic group having one nitrogen atom and oneoxygen atom in the ring

(the 4- to 6-membered aliphatic heterocyclic group having one nitrogenatom in the ring and the 6-membered aliphatic heterocyclic group havingone nitrogen atom and one oxygen atom in the ring each optionally having1 or 2 substituents independently selected from group C describedbelow),

group C: a halogen atom, a C₁-C₆ alkyl group, and a hydroxy-C₁-C₆ alkylgroup, and

group D: an amino group and a halogen atom.

(2) A compound according to (1) or a pharmacologically acceptable saltthereof, wherein in the formula (I),

Q represents an oxygen atom.

(3) A compound according to (1) or a pharmacologically acceptable saltthereof, wherein in the formula (I),

Q represents R^(a)N, wherein

R^(a) represents a hydrogen atom or a C₁-C₆ alkyl group.

(4) A compound according to any one of (1) to (3) or a pharmacologicallyacceptable salt thereof, wherein in the formula (I),

Y³ represents a hydrogen atom.

(5) A compound according to any one of (1) to (4) or a pharmacologicallyacceptable salt thereof, wherein in the formula (I),

G is represented by the following formula (III):

wherein

V represents CR^(e) or a nitrogen atom; and

R⁴, R⁵, R⁶, and R^(e) each independently represent a hydrogen atom, ahalogen atom, a cyano group, or a 5- or 6-membered heteroaryl grouphaving, in the ring, 1 to 3 heteroatoms independently selected from thegroup consisting of a nitrogen atom, an oxygen atom, and a sulfur atom

(provided that when V represents CR^(e), at least one of R⁴, R⁵, R⁶, andR^(e) represents a hydrogen atom).

(6) A compound according to any one of (1) to (4) or a pharmacologicallyacceptable salt thereof, wherein in the formula (I),

G is represented by the following formula (IV):

wherein

U represents a nitrogen atom or CH;

R⁷ represents a hydrogen atom or a C₁-C₆ alkyl group; and

R⁸ represents a hydrogen atom, a C₁-C₆ alkyl group, or a halogen atom.

(7) A compound according to any one of (1) to (4) or a pharmacologicallyacceptable salt thereof, wherein in the formula (I),

G is any of the following G^(a) to G^(e):

(8) A compound according to any one of (1) to (7) or a pharmacologicallyacceptable salt thereof, wherein in the formula (I),Y⁴ represents a group selected from group A¹:group A¹: —O-M¹, —S-M¹, and —NH-M¹

(M¹ represents a C₁-C₆ alkyl group having 1 or 2 substituentsindependently selected from group B¹ described below, an amino-C₃-C₆cycloalkyl group, a 4- to 6-membered aliphatic heterocyclic group havingone nitrogen atom in the ring, or a 5- or 6-membered aliphaticheterocyclic group substituted by 1 or 2 halogen atoms and having onenitrogen atom in the ring), group B¹: an amino group, a hydroxy group, aC₁-C₆ alkylamino group, a di-C₁-C₆ alkylamino group, a C₃-C₆cycloalkylamino group, an amino-C₃-C₆ cycloalkyl group, a hydroxy-C₁-C₆alkylamino group, and a 4- to 6-membered aliphatic heterocyclic grouphaving one nitrogen atom in the ring

(the 4- to 6-membered aliphatic heterocyclic group having one nitrogenatom in the ring optionally having 1 or 2 substituents independentlyselected from group C¹ described below), and

group C¹: a halogen atom, a C₁-C₆ alkyl group, and a hydroxy-C₁-C₆ alkylgroup.

(9) A compound according to any one of (1) to (7) or a pharmacologicallyacceptable salt thereof, wherein in the formula (I),

Y⁴ represents —O-M², wherein

M² is any of the following M^(2a) to M²¹:

(10) A compound according to any one of (1) to (7) or apharmacologically acceptable salt thereof, wherein in the formula (I),Y⁴ is represented by the following formula (V):

whereinn represents 1 or 2; andR²¹ and R³¹ each independently represents a hydrogen atom, an aminogroup, a C₁-C₆ alkyl group, an amino-C₁-C₆ alkyl group, or a C₁-C₆alkylamino group.(11) A compound according to any one of (1) to (7) or apharmacologically acceptable salt thereof, wherein in the formula (I),Y⁴ is the following Y^(a) or Y^(b):

(12) Any one compound or pharmacologically acceptable salt thereofselected from the following group:

-   N-[(1R)-1-(3-fluorophenyl)ethyl]-3-[4-[[(2S)-pyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2-b]pyridazin-6-amine,-   N-[(1R)-1-(3-fluorophenyl)ethyl]-3-[4-[2-(methylamino)ethoxy]phenyl]imidazo[1,2-b]pyridazin-6-amine,-   3-[4-[[(2S)-azetidin-2-yl]methoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine,-   3-[4-[(2R)-2-aminopropoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine,-   3-[4-[(2S)-2-aminopropoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine,-   (4S)-4-amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one,-   (4S)-4-amino-1-[4-[6-[[(1R)-1-(3-fluorophenyl)ethyl]amino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one,-   (4S)-4-amino-1-[5-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]pyrrolidin-2-one,-   (4S)-4-amino-1-[4-[6-[(3-fluorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one,    and-   (4S)-4-amino-1-[4-[6-[(3-fluorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]-3-methoxyphenyl]pyrrolidin-2-one.-   (13)    N-[(1R)-1-(3-Fluorophenyl)ethyl]-3-[4-[[(2S)-pyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2-b]pyridazin-6-amine.-   (14)    3-[4-[(2R)-2-Aminopropoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine.-   (15)    (4S)-4-Amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one.-   (16)    (4S)-4-Amino-1-[4-[6-[(3-fluorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one.-   (17)    N-[(1R)-1-(3-Fluorophenyl)ethyl]-3-[4-[[(2S)-pyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2-b]pyridazin-6-amine    maleate.-   (18)    N-[(1R)-1-(3-Fluorophenyl)ethyl]-3-[4-[[(2S)-pyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2-b]pyridazin-6-amine    adipate.-   (19)    3-[4-[(2R)-2-Aminopropoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine    methanesulfonate.-   (20)    3-[4-[(2R)-2-Aminopropoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine    adipate.-   (21)    (4S)-4-Amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one    benzenesulfonate.-   (22)    (4S)-4-Amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one    hydrochloride.-   (23)    (4S)-4-Amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one    adipate.-   (24)    (4S)-4-Amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one    lactate.-   (25)    (4S)-4-Amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one    benzoate.-   (26)    (4S)-4-Amino-1-[4-[6-[(3-fluorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one    benzenesulfonate.-   (27)    (4S)-4-Amino-1-[4-[6-[(3-fluorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one    adipate.-   (28)    (4S)-4-Amino-1-[4-[6-[(3-fluorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one    camphorate.-   (29) A ROS1 kinase enzyme activity inhibitor comprising a compound    according to any one of (1) to (28) or a pharmacologically    acceptable salt thereof as an active ingredient.-   (30) An NTRK kinase enzyme activity inhibitor comprising a compound    according to any one of (1) to (28) or a pharmacologically    acceptable salt thereof as an active ingredient.-   (31) A pharmaceutical composition comprising a compound according to    any one of (1) to (28) or a pharmacologically acceptable salt    thereof as an active ingredient.-   (32) An antitumor agent comprising a compound according to any one    of (1) to (28) or a pharmacologically acceptable salt thereof as an    active ingredient.-   (33) An antitumor agent according to (32), wherein the tumor is    hematological malignant tumor (leukemia, lymphoma, or multiple    myeloma), brain tumor, head and neck cancer, esophageal cancer,    gastric cancer, appendix cancer, colon cancer, anus cancer,    gallbladder cancer, bile duct cancer, pancreatic cancer,    gastrointestinal stromal tumor, lung cancer, liver cancer,    mesothelioma, thyroid cancer, kidney cancer, prostate cancer,    neuroendocrine tumor, melanoma, breast cancer, uterine body cancer,    uterine cervical cancer, ovary cancer, osteosarcoma, soft tissue    sarcoma, Kaposi's sarcoma, myosarcoma, kidney cancer, urinary    bladder cancer, or testicular cancer.-   (34) A therapeutic agent for a tumor having a detectable increase in    the expression level of ROS1 gene, comprising a compound according    to any one of (1) to (28) or a pharmacologically acceptable salt    thereof as an active ingredient.-   (35) A therapeutic agent for a tumor having a detectable increase in    the expression level of NTRK gene, comprising a compound according    to any one of (1) to (28) or a pharmacologically acceptable salt    thereof as an active ingredient.-   (36) A therapeutic agent for a tumor having a detectable expression    of ROS1 fusion gene, comprising a compound according to any one    of (1) to (28) or a pharmacologically acceptable salt thereof as an    active ingredient.-   (37) A therapeutic agent for a tumor having a detectable expression    of NTRK fusion gene, comprising a compound according to any one    of (1) to (28) or a pharmacologically acceptable salt thereof as an    active ingredient.-   (38) A therapeutic agent for a tumor that is treatable by the    inhibition of ROS1 kinase enzyme activity, comprising a compound    according to any one of (1) to (28) or a pharmacologically    acceptable salt thereof as an active ingredient.-   (39) A therapeutic agent for a tumor that is treatable by the    inhibition of NTRK kinase enzyme activity, comprising a compound    according to any one of (1) to (28) or a pharmacologically    acceptable salt thereof as an active ingredient.-   (40) A method for treating a tumor, comprising administering a    compound according to any one of (1) to (28) or a pharmacologically    acceptable salt thereof.-   (41) A method for treating a tumor according to (40), wherein the    tumor is hematological malignant tumor (leukemia, lymphoma, or    multiple myeloma), brain tumor, head and neck cancer, esophageal    cancer, gastric cancer, appendix cancer, colon cancer, anus cancer,    gallbladder cancer, bile duct cancer, pancreatic cancer,    gastrointestinal stromal tumor, lung cancer, liver cancer,    mesothelioma, thyroid cancer, prostate cancer, neuroendocrine tumor,    melanoma, breast cancer, uterine body cancer, uterine cervical    cancer, ovary cancer, osteosarcoma, soft tissue sarcoma, Kaposi's    sarcoma, myosarcoma, kidney cancer, urinary bladder cancer, or    testicular cancer.-   (42) A method for treating a tumor having a detectable increase in    the expression level of ROS1 gene, comprising administering a    compound according to any one of (1) to (28) or a pharmacologically    acceptable salt thereof as an active ingredient.-   (43) An agent for treating a tumor having a detectable increase in    the expression level of NTRK gene, comprising a compound according    to any one of (1) to (28) or a pharmacologically acceptable salt    thereof as an active ingredient.-   (44) A method for treating a tumor having a detectable expression of    ROS1 fusion gene, comprising administering a compound according to    any one of (1) to (28) or a pharmacologically acceptable salt    thereof.-   (45) A method for treating a tumor having a detectable expression of    NTRK fusion gene, comprising administering a compound according to    any one of (1) to (28) or a pharmacologically acceptable salt    thereof.-   (46) A method for treating a tumor that is treatable by the    inhibition of ROS1 kinase enzyme activity, comprising administering    a compound according to any one of (1) to (28) or a    pharmacologically acceptable salt thereof.-   (47) A method for treating a tumor that is treatable by the    inhibition of NTRK kinase enzyme activity, comprising a compound    according to any one of (1) to (28) or a pharmacologically    acceptable salt thereof as an active ingredient.

Advantageous Effects of Invention

The compounds of the present invention or pharmacologically acceptablesalts thereof have a potent ROS1 kinase enzyme activity inhibitoryeffect and NTRK kinase enzyme inhibitory activity and suppress cellgrowth. Thus, the compounds of the present invention orpharmacologically acceptable salts thereof are useful as antitumoragents, particularly, therapeutic agents for a tumor such ashematological malignant tumor (leukemia, lymphoma, or multiple myeloma),brain tumor, head and neck cancer, esophageal cancer, gastric cancer,appendix cancer, colon cancer, anus cancer, gallbladder cancer, bileduct cancer, pancreatic cancer, gastrointestinal stromal tumor, lungcancer, liver cancer, mesothelioma, thyroid cancer, prostate cancer,neuroendocrine tumor, melanoma, breast cancer, uterine body cancer,uterine cervical cancer, ovary cancer, osteosarcoma, soft tissuesarcoma, Kaposi's sarcoma, myosarcoma, kidney cancer, urinary bladdercancer, and testicular cancer. The compounds of the present invention orpharmacologically acceptable salts thereof are effective as therapeuticdrugs for tumors having a detectable increase in the expression level ofROS1 gene and/or having a detectable expression of ROS1 fusion gene, ortumors having a detectable increase in the expression level of NTRK geneand/or having a detectable expression of NTRK fusion gene, among thesetumors.

DESCRIPTION OF EMBODIMENTS

In the present invention, “halogen atom” refers to a fluorine atom, achlorine atom, a bromine atom, or an iodine atom.

In the present invention, “C₁-C₆ alkyl group” refers to a linear orbranched alkyl group having 1 to 6 carbon atoms. Examples thereofinclude a methyl group, an ethyl group, a propyl group, an isopropylgroup, a butyl group, an isobutyl group, a s-butyl group, a t-butylgroup, a pentyl group, an isopentyl group, a 2-methylbutyl group, aneopentyl group, a 1-ethylpropyl group, a hexyl group, an isohexylgroup, and a 4-methylpentyl group.

In the present invention, “C₁-C₆ alkoxy group” refers to a C₁-C₆ alkoxygroup formed from the above-described C₁-C₆ alkyl group. Examplesthereof include a methoxy group, an ethoxy group, a n-propoxy group, anisopropoxy group, a butoxy group, an isobutoxy group, a s-butoxy group,a t-butoxy group, a pentoxy group, an isopentoxy group, a 2-methylbutoxygroup, hexyloxy, and an isohexyloxy group.

In the present invention, “amino-C₁-C₆ alkyl group” means theabove-described C₁-C₆ alkyl group substituted by one amino group.Examples thereof include an aminomethyl group, a 1-aminoethyl group, a2-aminoethyl group, a 1-aminopropyl group, a 2-aminopropyl group, a3-aminopropyl group, a 1-aminobutyl group, a 2-aminobutyl group, a3-aminobutyl group, and a 4-aminobutyl group.

In the present invention, “halo-C₁-C₆ alkyl group” means theabove-described C₁-C₆ alkyl group substituted by one above-describedhalogen atom. Examples thereof include a fluoromethyl group, achloromethyl group, a bromomethyl group, a 2-fluoroethyl group, a2-chloroethyl group, a 3-fluoropropyl group, and a 3-chloropropyl group.

In the present invention, “fluoro-C₁-C₆ alkyl group” means theabove-described C₁-C₆ alkyl group substituted by one fluorine atom.Examples thereof include a fluoromethyl group, a 2-fluoroethyl group,and a 3-fluoropropyl group.

In the present invention, “dihalo-C₁-C₆ alkyl group” means theabove-described C₁-C₆ alkyl group substituted by two identical ordifferent above-described halogen atoms. Examples thereof include adifluoromethyl group, a dichloromethyl group, a dibromomethyl group, a2,2-difluoroethyl group, a 2,2-dichloroethyl group, a 3,3-difluoropropylgroup, and a 3,3-dichloropropyl group.

In the present invention, “trihalo-C₁-C₆ alkyl group” means theabove-described C₁-C₆ alkyl group substituted by three identical ordifferent above-described halogen atoms. Examples thereof include atrifluoromethyl group, a trichloromethyl group, a tribromomethyl group,a 2,2,2-trifluoroethyl group, a 2,2,2-trichloroethyl group, a3,3,3-trifluoropropyl group, and a 3,3,3-trichloropropyl group.

In the present invention, examples of a “C₃-C₆ cycloalkyl group” includea cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and acyclohexyl group.

In the present invention, “C₁-C₆ alkylamino group” means an amino groupsubstituted by one above-described C₁-C₆ alkyl group. Examples thereofinclude a methylamino group, an ethylamino group, a propylamino group,an isopropylamino group, a butylamino group, an isobutylamino group, as-butylamino group, a t-butylamino group, a pentylamino group, anisopentylamino group, a 2-methylbutylamino group, a neopentylaminogroup, a 1-ethylpropylamino group, a hexylamino group, and anisohexylamino group.

In the present invention, “di-C₁-C₆ alkylamino group” means an aminogroup substituted by two identical or different above-described C₁-C₆alkyl groups. Examples thereof include a dimethylamino group, adiethylamino group, a dipropylamino group, a diisopropylamino group, adibutylamino group, a diisobutylamino group, a dipentylamino group, adineopentylamino group, a dihexylamino group, a N-ethyl-N-methylaminogroup, a N-methyl-N-propylamino group, a N-isopropyl-N-methylaminogroup, a N-butyl-N-methylamino group, a N-isobutyl-N-methylamino group,a N-ethyl-N-propylamino group, a N-ethyl-N-isopropylamino group, aN-butyl-N-ethylamino group, and a N-ethyl-N-isopentylamino group.

In the present invention, “C₃-C₆ cycloalkylamino group” means an aminogroup substituted by one above-described C₃-C₆ cycloalkyl group.Examples thereof include a cyclopropylamino group, a cyclobutylaminogroup, a cyclopentylamino group, and a cyclohexylamino group.

In the present invention, “amino-C₃-C₆ cycloalkyl group” means oneabove-described C₃-C₆ cycloalkyl group substituted by one amino group.Examples thereof include a 1-aminocyclopropyl group, a2-aminocyclopropyl group, a 1-aminocyclobutyl group, a 2-aminocyclobutylgroup, a 3-aminocyclobutyl group, a 1-aminocyclopentyl group, a2-aminocyclopentyl group, a 3-aminocyclopentyl group, a1-aminocyclohexyl group, a 2-aminocyclohexyl group, a 3-aminocyclohexylgroup, and a 4-aminocyclohexyl group.

In the present invention, “hydroxy-C₁-C₆ alkyl group” means theabove-described C₁-C₆ alkyl group substituted by one hydroxy group.Examples thereof include a hydroxymethyl group, a 1-hydroxyethyl group,a 2-hydroxyethyl group, a 1-hydroxypropyl group, a 2-hydroxypropylgroup, a 3-hydroxypropyl group, a 1-hydroxy-1-methyl-ethyl group, a2-hydroxy-methyl-ethyl group, a 1-hydroxybutyl group, a 2-hydroxybutylgroup, a 3-hydroxybutyl group, a 4-hydroxybutyl group, a1-hydroxy-2-methyl-propyl group, a 2-hydroxy-2-methyl-propyl group, a3-hydroxy-2-methyl-propyl group, a 1-hydroxy-1-methyl-propyl group, a1-(hydroxymethyl)propyl group, a 2-hydroxy-1-methyl-propyl group, a3-hydroxy-1-methyl-propyl group, a 1-hydroxypentyl group, a2-hydroxypentyl group, a 3-hydroxypentyl group, a 4-hydroxypentyl group,and a 5-hydroxypentyl group.

In the present invention, “hydroxy-C₁-C₆ alkylamino group” means anamino group substituted by one above-described hydroxy-C₁-C₆ alkylgroup. Examples thereof include a hydroxymethylamino group, a2-hydroxyethylamino group, and a 3-hydroxypropylamino group.

In the present invention, “heteroaryl group” means a group derived froma 5- or 6-membered monocyclic aromatic compound containing 1 or 4 atomseach independently selected from the group consisting of a nitrogenatom, an oxygen atom, and a sulfur atom as ring-constituting atoms otherthan carbon. Examples thereof include a furyl group, a thienyl group, apyrrolyl group, an oxazolyl group, an isoxazolyl group, a thiazolylgroup, an isothiazolyl group, an imidazolyl group, a pyrazolyl group, apyridyl group, a pyrazyl group, a pyrimidinyl group, and a pyridazinylgroup.

In the present invention, “heteroarylene group” means a divalent groupderived from the above-described heteroaryl group. Examples thereofinclude a thienylene group, a pyrrolylene group, a thiazolylene group,an imidazolylene group, a pyrazolylene group, a pyridylene group, apyrazylene group, a pyrimidylene group, and a pyridazylene group.

In the present invention, “aliphatic heterocyclic group” means a groupderived from an aliphatic cyclic compound containing 1 or 4 atoms eachindependently selected from the group consisting of a nitrogen atom, anoxygen atom, and a sulfur atom as ring-constituting atoms other thancarbon. Examples thereof include an oxiranyl group, an aziridinyl group,a thiiranyl group, an oxetanyl group, an azetidinyl group, a thietanylgroup, a tetrahydrofuranyl group, a pyrrolidinyl group, atetrahydrothiophenyl group, a tetrahydropyranyl group, atetrahydrothiopyranyl group, a morpholino group, a morpholinyl group,and a piperazinyl group.

In the present invention, the term “tumor” is not limited to malignanttumor and includes every type of tumor, for example, carcinoma, sarcoma,and benign tumor. Particularly, a malignant tumor may be expressed as“cancer”.

In the present invention, “increase in the expression level of ROS1gene” means that the mRNA expression level or protein expression levelof the ROS1 gene has been increased by enhanced gene transcriptionactivity, promoted translation, suppressed proteolysis, improved proteinstabilization, etc.

In the present invention, “expression of ROS1 fusion gene” means thatthe ROS1 fusion gene has been formed and expressed as a result of thefusion between the ROS1 gene and another gene (e.g., FIG gene, SLC34A2gene, or CD74 gene).

In the present invention, “chromosomal translocation of ROS1 gene”refers to a positional mutation in a chromosome containing the ROS1gene.

In the present invention, “ROS1 pathway” refers to a pathway throughwhich ROS1 and subsequently STAT3, ERK, SHP2, and the like arephosphorylated, leading to the growth, survival, etc. of cancer cells.

In the present invention, “ROS1 kinase enzyme activity inhibitoryeffect” is indicated by the inhibition of ROS1 kinase and/or theinhibition of ROS1 autophosphorylation activity.

In the present invention, “increase in the expression level of NTRKgene” means that the mRNA expression level or protein expression levelof the NTRK gene has been increased by enhanced gene transcriptionactivity, promoted translation, suppressed proteolysis, improved proteinstabilization, etc.

In the present invention, “expression of NTRK fusion gene” means thatthe NTRK fusion gene has been formed and expressed as a result of thefusion between the NTRK gene and another gene (e.g., TPM3 gene, TPRgene, or ETV6 gene).

In the present invention, “NTRK kinase enzyme activity inhibitoryeffect” is indicated by an NTRK autophosphorylation activity inhibitoryeffect.

Next, each substituent in the general formula (I) will be described.

R¹ represents a hydrogen atom or a C₁-C₆ alkyl group.

Preferably, R¹ is a hydrogen atom or a methyl group.

Q represents an oxygen atom or R^(a)N.

In this context, R^(a) represents a hydrogen atom or a C₁-C₆ alkylgroup.

Preferably, R^(a) is a hydrogen atom or a methyl group.

G represents a phenyl group or a 5- or 6-membered heteroaryl grouphaving, in the ring, 1 or 2 heteroatoms independently selected from thegroup consisting of a nitrogen atom, an oxygen atom, and a sulfur atom.The phenyl group and the 6-membered heteroaryl group may have 1 to 3substituents independently selected from the group consisting of ahalogen atom, a cyano group, a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group,and a trihalo-C₁-C₆ alkyl group. The 5-membered heteroaryl group mayhave 1 or 2 substituents independently selected from the groupconsisting of a halogen atom, a cyano group, a C₁-C₆ alkyl group, aC₁-C₆ alkoxy group, a monohalo-C₁-C₆ alkyl group, a dihalo-C₁-C₆ alkylgroup, and a trihalo-C₁-C₆ alkyl group.

In one aspect, G is a phenyl group, a pyridyl group, or a pyrazyl group.The phenyl group, the pyridyl group, or the pyrazyl group isunsubstituted or may have 1 to 3 substituents independently selectedfrom the group consisting of a halogen atom, a cyano group, a C₁-C₆alkyl group, a C₁-C₆ alkoxy group, and a trihalo-C₁-C₆ alkyl group.

Preferably, G is a phenyl group, a pyridyl group or a pyrazyl group. Thephenyl group, the pyridyl group, or the pyrazyl group is unsubstitutedor substituted by one fluorine atom, two fluorine atoms, one chlorineatom, one fluorine atom and one chlorine atom, one fluorine atom and onemethyl group, a cyano group, a methyl group, or a trifluoromethyl group.

In another aspect, G is a thiazolyl group, or a pyrazolyl group. Thethiazolyl group or the pyrazolyl group is unsubstituted or may have 1 or2 substituents independently selected from the group consisting of ahalogen atom, a cyano group, a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group,a monohalo-C₁-C₆ alkyl group, a dihalo-C₁-C₆ alkyl group, and atrihalo-C₁-C₆ alkyl group.

Preferably, G is a pyrazolyl group. The pyrazolyl group is substitutedby one fluorine atom, one chlorine atom, one methyl group, onedifluoromethyl group, one trifluoromethyl group, two methyl groups, onechlorine atom and one methyl group, one methyl group and onedifluoromethyl group, or one methyl group and one trifluoromethyl group.

In a more preferred aspect, G is any one of the following G^(a) toG^(e):

T represents a nitrogen atom or CR^(b).

In this context, R^(b) represents a hydrogen atom, a halogen atom, aC₁-C₆ alkyl group, a C₁-C₆ alkoxy group, or a cyano group.

Preferably, T is CR^(b), and R^(b) is a hydrogen atom or a fluorineatom.

Y¹ and Y² each independently represents a hydrogen atom, a halogen atom,a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, or a cyano group.

Preferably, Y¹ and Y² are each independently a hydrogen atom or afluorine atom.

Y³ and Y⁴ each independently represents a hydrogen atom, a groupselected from the above-described group A, or a group represented by theabove-described formula (II), provided that any one of Y³ and Y⁴inevitably represents a hydrogen atom, and the other group represents agroup other than a hydrogen atom.

In a preferred aspect, for example, Y³ represents a hydrogen atom, andY⁴ represents —O-M². In this context, M² is any one of the followingM^(2a) to M²¹:

In a more preferred aspect, for example, Y³ represents a hydrogen atom,and Y⁴ represents —O-M³. In this context, M³ is any one of the followingM^(3a) to M^(3q):

In another preferred aspect, Y³ represents a hydrogen atom, and Y⁴ isthe following Y^(a) or Y^(b):

In a more preferred aspect, Y³ represents a hydrogen atom, and Y⁴ is thefollowing Y^(c) or Y^(d):

According to a preferred aspect, the compound represented by the generalformula (I) is any one compound selected from the following group or apharmacologically acceptable salt thereof:

-   N-[(1R)-1-(3-fluorophenyl)ethyl]-3-[4-[[(2S)-pyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2-b]pyridazin-6-amine,-   N-[(1R)-1-(3-fluorophenyl)ethyl]-3-[4-[2-(methylamino)ethoxy]phenyl]imidazo[1,2-b]pyridazin-6-amine,-   3-[4-[[(2S)-azetidin-2-yl]methoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine,-   3-[4-[(2R)-2-aminopropoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine,-   3-[4-[(2S)-2-aminopropoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine,-   (4S)-4-amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one,-   (4S)-4-amino-1-[4-[6-[[(1R)-1-(3-fluorophenyl)ethyl]amino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one,-   (4S)-4-amino-1-[5-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]pyrrolidin-2-one,-   (4S)-4-amino-1-[4-[6-[(3-fluorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one,    and-   (4S)-4-amino-1-[4-[6-[(3-fluorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]-3-methoxyphenyl]pyrrolidin-2-one.

The compounds represented by the general formula (I) of the presentinvention can form pharmaceutically acceptable salts, if desired. Theterm pharmaceutically acceptable salt refers to a salt that has nosignificant toxicity and can be used as a medicine. A compoundrepresented by the general formula (I) of the present invention can beconverted to a salt through reaction with an acid, when having a basicgroup.

Examples of the salt based on the basic group can include: inorganicacid salts such as hydrohalides (e.g., hydrofluoride, hydrochloride,hydrobromide, and hydroiodide), nitrate, perchlorate, sulfate, andphosphate; organic acid salts such as C₁-C₆ alkylsulfonates (e.g.,methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate),arylsulfonates (e.g., benzenesulfonate and p-toluenesulfonate), acetate,malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate,adipate, and maleate; and amino acid salts such as glycine salt, lysinesalt, arginine salt, ornithine salt, glutamate, and aspartate.

The compounds represented by the general formula (I) of the presentinvention or salts thereof, when left in the atmosphere orrecrystallized, may form a hydrate by absorbing water molecules. Suchhydrates are also included in the salts of the present invention.

The compounds represented by the general formula (I) of the presentinvention or salts thereof, when left in a solvent or recrystallized,may form a solvate by absorbing a certain kind of solvent. Such solvatesare also included in the salts of the present invention.

The compounds represented by the general formula (I) of the presentinvention or pharmacologically acceptable salts thereof encompass allisomers (diastereomers, optical isomers, geometric isomers, rotationalisomers, etc.).

These isomers of the compounds of the present invention and mixtures ofthese isomers are all represented by a single formula, i.e., the generalformula (I). Thus, the present invention encompasses all of theseisomers and even mixtures of these isomers at any ratio.

The compounds of the present invention may contain isotope(s) of one ormore atoms constituting such compounds at a nonnatural ratio. Examplesof the isotope include deuterium (²H), tritium (³H), iodine-125 (¹²⁵I),and carbon-14 (¹⁴C). Alternatively, the compounds may be radiolabeledwith a radioisotope, for example, tritium (³H), iodine-125 (¹²⁵I), orcarbon-14 (¹⁴C). Such radiolabeled compounds are useful as therapeuticor prophylactic agents, research reagents, for example, assay reagents,and diagnostic agents, for example, in vivo diagnostic imaging agents.All isotopic variants of the compounds of the present invention fallwithin the scope of the present invention, regardless of beingradioactive or not.

The ROS1 kinase enzyme activity inhibitory effect of the compounds ofthe present invention can be assayed by the methods of Test Example 1 or2. The NTRK activity inhibitory effect of the compounds of the presentinvention can be assayed by the method of Test Example 3.

The cell growth inhibitory activity of the compounds of the presentinvention can be examined using a growth inhibition test method usuallyused by those skilled in the art. The cell growth inhibitory activitycan be determined, for example, as described below in Test Example 4, bythe comparison of the degree of cell growth in the presence of and inthe absence of a test compound. The degree of growth can be examinedusing, for example, a test system for assaying live cells. Examples ofthe method for assaying live cells include a [³H]-thymidine uptake test,a BrdU method, and MTT assay.

Also, the in vivo antitumor activity of the compounds of the presentinvention can be examined using an antitumor test method usually used bythose skilled in the art. For example, various tumor cells aretransplanted to mice, rats, or the like. After confirmation ofsuccessful engraftment of the transplanted cells, the compound of thepresent invention is administered, for example, orally or intravenously,to the animals. A few days to a few weeks later, tumor growth in adrug-unadministered group can be compared with tumor growth in thecompound-administered group to confirm the in vivo antitumor activity ofthe compound of the present invention.

The compounds of the present invention can be used in the treatment of atumor, for example, hematological malignant tumor (leukemia, lymphoma,or multiple myeloma), brain tumor, head and neck cancer, esophagealcancer, gastric cancer, appendix cancer, colon cancer, anus cancer,gallbladder cancer, bile duct cancer, pancreatic cancer,gastrointestinal stromal tumor, lung cancer, liver cancer, mesothelioma,thyroid cancer, kidney cancer, prostate cancer, neuroendocrine tumor,melanoma, breast cancer, uterine body cancer, uterine cervical cancer,ovary cancer, osteosarcoma, soft tissue sarcoma, Kaposi's sarcoma,myosarcoma, kidney cancer, urinary bladder cancer, or testicular cancer.Preferably, the compounds of the present invention are used in thetreatment of non-small cell lung cancer, bile duct cancer, or braintumor.

It has been suggested that the ROS1 pathway is involved in the growth,survival, etc. of cancer. Hence, the compounds of the present inventionare preferably used for a tumor with an activated ROS1 pathway.

Examples of a tumor with an activated ROS1 pathway include a tumorhaving increase in the expression level of ROS1 gene, a tumor in whichthe chromosomal translocation of ROS1 has occurred, and a tumor in whichROS1 fusion gene has been formed and activated as a result of the fusionbetween the ROS1 gene and another gene (e.g., FIG gene, SLC34A2 gene, orCD74 gene). Non-small cell lung cancer, bile duct cancer, and braintumor are known as tumors with an activated ROS1 pathway.

It has also been suggested that the overexpression, fusion gene, andactivation, etc. of NTRK is involved in the growth, survival, etc. ofcancer. Hence, the compounds of the present invention are preferablyused for a tumor with activated NTRK.

Examples of a tumor with activated NTRK include a tumor having anincrease in the expression level of NTRK gene. Prostate cancer and thelike are known as tumors with activated NTRK.

The activated ROS1 pathway can be confirmed on the basis of gene/proteinamplification or mutation of ROS1, ROS1 fusion gene, or the like, ROS1phosphorylation, STAT3 phosphorylation, ERK phosphorylation, SHP2phosphorylation, AKT phosphorylation, or the like in the test tissues(collected by, for example, blood collection or biopsy) of patients, orthe activated NTRK can be confirmed on the basis of gene/proteinamplification, etc. of NTRK or NTRK fusion gene in the test tissues(collected by, for example, blood collection or biopsy) of patients,using methods known in the art such as Southern blotting, Northernblotting, Western blotting, ELISA, DNA chips, FISH assay, histologicalimmunostaining, and analysis using other gene analysis methods known inthe art {e.g., PCR, LCR (ligase chain reaction), SDA (stranddisplacement amplification), NASBA (nucleic acid sequence-basedamplification), ICAN (isothermal and chimeric primer-initiatedamplification), and LAMP (loop-mediated isothermal amplification)}, orpathological approaches.

The compounds of the present invention may be used in combination withan additional antitumor agent. Examples thereof include antitumorantibiotics, antitumor plant constituents, BRMs (biological responsemodifiers), hormones, vitamins, antitumor antibodies, molecular targetdrugs, and other antitumor agents.

More specifically, examples of alkylating agents include: alkylatingagents such as nitrogen mustard, nitrogen mustard N-oxide, andchlorambucil; aziridine alkylating agents such as carboquone andthiotepa; epoxide alkylating agents such as dibromomannitol anddibromodulcitol; nitrosourea alkylating agents such as carmustine,lomustine, semustine, nimustine hydrochloride, streptozocin,chlorozotocin, and ranimustine; and other agents such as busulfan,improsulfan tosylate, and dacarbazine.

Examples of various metabolic antagonists include: purine metabolicantagonists such as 6-mercaptopurine, 6-thioguanine, and thioinosine;pyrimidine metabolic antagonists such as fluorouracil, tegafur,tegafur-uracil, carmofur, doxifluridine, broxuridine, cytarabine, andenocitabine; and folic acid metabolic antagonists such as methotrexateand trimetrexate.

Examples of antitumor antibiotics include: antitumor anthracyclineantibiotics such as mitomycin C, bleomycin, peplomycin, daunorubicin,aclarubicin, doxorubicin, pirarubicin, THP-adriamycin,4′-epidoxorubicin, and epirubicin; and other antibiotics such aschromomycin A3 and actinomycin D.

Examples of antitumor plant constituents include: vinca alkaloids suchas vindesine, vincristine, and vinblastine; taxanes such as paclitaxeland docetaxel; and epipodophyllotoxins such as etoposide and teniposide.

Examples of BRMs include tumor necrosis factors and indomethacin.

Examples of hormones include hydrocortisone, dexamethasone,methylprednisolone, prednisolone, prasterone, betamethasone,triamcinolone, oxymetholone, nandrolone, metenolone, fosfestrol,ethinylestradiol, chlormadinone, and medroxyprogesterone.

Examples of vitamins include vitamin C and vitamin A.

Examples of antitumor antibodies and molecular target drugs includetrastuzumab, rituximab, cetuximab, nimotuzumab, denosumab, bevacizumab,infliximab, imatinib mesilate, gefitinib, erlotinib, sunitinib,lapatinib, and sorafenib.

Examples of other antitumor agents include cisplatin, carboplatin,oxaliplatin, tamoxifen, camptothecin, ifosfamide, cyclophosphamide,melphalan, L-asparaginase, aceglatone, sizofiran, picibanil,procarbazine, pipobroman, neocarzinostatin, hydroxyurea, ubenimex, andkrestin.

Next, a typical method for producing the compounds represented by thegeneral formula (I) will be described. The compounds of the presentinvention can be produced by various production methods. The productionmethod shown below is given for illustrative purposes. It should beunderstood that the present invention is not limited by this example.The compounds represented by the general formula (I) and intermediatesfor production thereof can be produced through the use of variousreactions known in the art as described below. In this respect,functional groups in starting materials or intermediates may beprotected with appropriate protective groups. Examples of suchfunctional groups can include a hydroxy group, a carboxy group, and anamino group. For the types of the protective groups and conditions forthe introduction and removal of these protective groups, see, forexample, Protective Groups in Organic Synthesis (T. W. Greene and P. G.M. Wuts, John Wiley & Sons, Inc., New York, 1991).

[Production Method]

In the reaction scheme, R^(a), G, Q, T, Y¹, and Y² are as defined above.In the reaction scheme, BA represents boronic acid or boronic acidester, organic tin, or the like.

In the reaction scheme, R¹¹ represents a hydrogen atom, a C₁-C₆ alkylgroup, a fluoro-C₁-C₆ alkyl group, or R¹². In this context, R¹²represents a C₁-C₆ alkyl group having a hydroxy group protected with aprotective group. Examples of the protective group include atert-butyldimethylsilyl group, a benzyl group, and an acetyl group.

In the reaction scheme, Y³¹ represents Y³ mentioned above, or when Y³has an amino group and/or a hydroxy group, Y³¹ represents an optionallyprotected amino group and/or hydroxy group in Y³. In the reactionscheme, Y⁴¹ represents Y⁴ mentioned above, or when Y⁴ has an amino groupand/or a hydroxy group, Y⁴¹ represents an optionally protected aminogroup and/or hydroxy group in Y⁴. Examples of the protective group forthe amino group include a benzyloxycarbonyl group, a tert-butoxycarbonylgroup, and a trityl group. Examples of the protective group for thehydroxy group include a tert-butyldimethylsilyl group, a benzyl group,and an acetyl group.

1. Conversion of Compound (1) to Compound (4)

The conversion of compound (1) to compound (4) is carried out through anucleophilic substitution reaction between the compound (1) and alcohol(2) or amine (3). The alcohol (2) or the amine (3) used in this reactionis commercially available or can be produced by a method known in theart.

For the substitution reaction using alcohol (2), the compound (1) can betreated with a stoichiometric amount of the alcohol (2) in the presenceof a base to obtain compound (4).

Examples of the base used can include inorganic bases (sodium hydride,etc.). The amount of the base used can be 1 to excess molar equivalentswith respect to the compound (1) and is preferably 1 to 2 molarequivalents. The amount of the alcohol (2) used can be 1 to excess molarequivalents with respect to the compound (1) and is preferably 1 to 1.5molar equivalents.

The solvent used in the reaction is an appropriate solvent that has noadverse effect on the reaction (e.g., N,N-dimethylformamide,N-methyl-2-pyrrolidone, tetrahydrofuran, or dimethyl sulfoxide) or amixed solvent thereof. The reaction temperature is preferably 0° C. to100° C., more preferably 0° C. to room temperature. The reaction time isusually preferably 1 minute to 24 hours, more preferably 10 minutes to 2hours.

For the above-described reaction using amine (3), the compound (1) canbe treated with a stoichiometric amount of the amine (3) in the presenceof a base or using an excessive amount of the amine (3) to obtaincompound (4).

Examples of the base used can include organic bases (e.g., triethylamineand diisopropylethylamine) and inorganic bases (potassium fluoride,etc.). The amount of the base used is preferably in the range of 2 to 10molar equivalents with respect to the compound (1). The amount of theamine (3) used may be 1 to 2 molar equivalents in the presence of thebase and is preferably in the range of 2 to 30 molar equivalents withrespect to the compound (1) in the absence of the base.

The solvent used in the reaction is an appropriate solvent that has noadverse effect on the reaction (e.g., N,N-dimethylformamide,N-methyl-2-pyrrolidone, or dimethyl sulfoxide) or a mixed solventthereof. The reaction temperature is preferably in the range of 80 to160° C. The reaction may be carried out by treatment in a sealed tube orunder microwave irradiation. The reaction time is usually preferablyapproximately 1 to 24 hours.

2. Conversion of Compound (4) to Compound (6)

The conversion of compound (4) to compound (6) is carried out through acoupling reaction between the compound (4) and compound (5) using anorganic chemical approach known in the art.

The coupling reaction is performed in the presence of an appropriateorganic boronic acid, organic tin, organic zinc, or organic magnesiumderivative, or the like (e.g., compound (5)) and an appropriatetransition metal catalyst (the transition metal catalyst is preferably apalladium catalyst, and examples thereof include a[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethanecomplex, dichlorobis(triphenylphosphine)palladium(II), andtetrakis(triphenylphosphine)palladium(0)) by the addition of, ifnecessary, an inorganic base or organic base (examples thereof includesodium carbonate, potassium carbonate, tripotassium phosphate, cesiumcarbonate, and diisopropylethylamine), a ligand (examples thereofinclude organic phosphorus compounds such as1,1′-bis(diphenylphosphino)ferrocene (dppf) and triphenylphosphine), anda reaction-promoting additive known in the art (examples thereof includelithium chloride and copper iodide) to the compound (4). The organicboronic acid derivative (5) is commercially available or can be producedby a method known in the art. Examples of references for the method forproducing the organic boronic acid derivative (5) and the couplingreaction can include “Chemical Reviews, 1995, 95, 2457-2483”.

The solvent used in the coupling reaction is an appropriate solvent thathas no adverse effect on the reaction (e.g., N,N-dimethylformamide,tetrahydrofuran, toluene, 1,4-dioxane, or water) or a mixed solventthereof. The reaction temperature is preferably 0° C. to 300° C., morepreferably room temperature to 200° C. (optimum temperature: 80° C. to100° C.). The coupling reaction may be performed by treatment in asealed tube or under microwave irradiation. The organic boronic acid orthe like and the base are each preferably used at 1 to excess molarequivalents with respect to the compound (4). The organic boronic acidor the like is more preferably used at 1 to 1.5 molar equivalents, andthe base is more preferably used at 1 to 5 molar equivalents. Thereaction time is preferably 1 minute to 60 hours, more preferably 5minutes to 24 hours.

3. Conversion of Compound (6) to Compound (I)

When the groups Y³¹ and/or Y⁴¹ in the compound (6) obtained by thisproduction method have functional groups such as an amino group or ahydroxy group and/or when the compound (6) has a hydroxy group on thegroup R¹¹, the functional groups such as an amino group or a hydroxygroup are preferably protected. The protective groups therefor can beremoved using methods generally used, as mentioned above. The aminogroup on the groups Y³¹ or/and Y⁴¹ can be converted to a substitutedamino group through alkylation or the like by a general method.

In the present invention, stereoisomers of the compounds represented bythe general formula (I) can be obtained using optically active startingcompounds or by the synthesis of the compounds according to the presentinvention using an asymmetric synthesis or asymmetric inductionapproach. Alternatively, the stereoisomers may be obtained by theisolation of the synthesized compounds according to the presentinvention using a conventional optical resolution or isolation method,if desired.

In the present invention, the compounds represented by the generalformula (I) encompass compounds labeled with isotopes or radioisotopes.Such labeled compounds can be produced, for example, using startingmaterials labeled with isotopes instead of the starting materials in theproduction method of the present invention.

The compounds represented by the general formula (I) of the presentinvention can be converted to salts through reaction with an acid, whenhaving a basic group.

The compounds represented by the general formula (I) of the presentinvention or the salts thereof, when left in the atmosphere orrecrystallized, may form a hydrate by absorbing water molecules.

The compounds represented by the general formula (I) of the presentinvention or the salts thereof, when left in a solvent or recrystallizedin a solvent, may form a solvate by absorbing a certain kind of solvent.

The compounds of the present invention or pharmacologically acceptablesalts thereof can be administered in various forms. Examples of thedosage form can include tablets, capsules, granules, emulsions, pills,powders, and syrups (solutions) for oral administration and injections(intravenous, intramuscular, subcutaneous, or intraperitonealadministration), drip infusions, and suppositories (rectaladministration) for parenteral administration. These variouspreparations can be formulated according to routine methods using aidsthat may be conventionally used in the field of pharmaceuticalformulation techniques such as excipients, binders, disintegrants,lubricants, corrigents, solubilizers, suspending agents, and coatingagents, in addition to the active ingredient.

For use as a tablet, examples of carriers that can be used include:excipients such as lactose, saccharose, sodium chloride, glucose, urea,starch, calcium carbonate, kaolin, crystalline cellulose, and silicicacid; binders such as water, ethanol, propanol, simple syrup, glucosesolutions, starch solutions, gelatin solutions, carboxymethylcellulose,shellac, methylcellulose, potassium phosphate, and polyvinylpyrrolidone;disintegrants such as dry starch, sodium alginate, agar powder,laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylenesorbitan fatty acid esters, sodium lauryl sulfate, monoglyceridestearate, starch, and lactose; disintegration inhibitors such assaccharose, stearin, cocoa butter, and hydrogenated oil; absorptionpromoters such as quaternary ammonium salts and sodium lauryl sulfate;moisturizing agents such as glycerin and starch; adsorbents such asstarch, lactose, kaolin, bentonite, and colloidal silicic acid; andlubricants such as purified talc, stearate, boric acid powder, andpolyethylene glycol. Alternatively, tablets coated in a conventionalmanner, for example, sugar-coated tablets, gelatin-coated tablets,enteric-coated tablets, film-coated tablets, double-layer tablets, andmultilayered tablets may be prepared, if necessary.

For use as a pill, examples of carriers that can be used include:excipients such as glucose, lactose, cocoa butter, starch, hydrogenatedplant oil, kaolin, and talc; binders such as gum arabic powder, powderedtragacanth, gelatin, and ethanol; and disintegrants such as laminaranand agar.

For use as a suppository, conventional carriers known in the art can bewidely used. Examples thereof can include polyethylene glycol, cocoabutter, higher alcohols, esters of higher alcohols, gelatin, andsemisynthetic glyceride.

For use as an injection, solutions, emulsions, or suspensions can beused. These solutions, emulsions, or suspensions are preferablysterilized and adjusted to be isotonic to blood. Any solvent that can beused as a medical diluent can be used without limitation in theproduction of these solutions, emulsions, or suspensions. Examplesthereof can include water, ethanol, propylene glycol, ethoxylatedisostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylenesorbitan fatty acid esters. In this case, each preparation may containcommon salt, glucose, or glycerin in an amount sufficient for preparingan isotonic solution. Also, each preparation may contain a conventionalsolubilizer, buffer, soothing agent, and the like.

These preparations may also contain a colorant, a preservative, afragrance, a flavor, a sweetener, and the like, if necessary, and mayfurther contain an additional pharmaceutical product.

The amount of the active ingredient compound contained in thepreparation is not particularly limited and is appropriately selected ina wide range. The composition usually contains 0.5 to 70% by weight,preferably 1 to 30% by weight of the compound with respect to the totalweight.

The amount of the compound used differs depending on the symptoms, age,etc. of the patient (warm-blooded animal, particularly, a human). Thedaily dose for oral administration to an adult human is 2000 mg(preferably 100 mg) as the upper limit and 0.1 mg (preferably 1 mg, morepreferably 10 mg) as the lower limit and is desirably administered onceto 6 times a day according to the symptoms.

EXAMPLES

Hereinafter, the present invention will be described in more detail withreference to Reference Examples, Examples, and Test Examples. However,the scope of the present invention is not intended to be limited bythese examples.

Elution for column chromatography in the Reference Examples and Exampleswas performed under observation by thin layer chromatography (TLC). Inthe TLC observation, silica gel 60F₂₅₄ or silica gel 60NH₂F₂₅₄Smanufactured by Merck & Co., Inc. was used as a TLC plate; the solventused as an elution solvent in column chromatography was used as adeveloping solvent; and a UV detector was adopted for a detectionmethod. Silica gel SK-85 (230 to 400 mesh) manufactured by Merck & Co.,Inc. or Chromatorex NH (200 to 350 mesh) manufactured by Fuji SilysiaChemical Ltd. was used as a silica gel for columns. In addition toconventional column chromatography apparatus, an automated purificationapparatus (YFLC-5404-FC) manufactured by Yamazen Corp. or an automatedpurification apparatus (HORIZON, SP1 or Isolera) manufactured by BiotageAB was appropriately used. Solvents designated in each Reference Exampleand Example were used as elution solvents. The abbreviations used inReference Examples and Examples have the following meanings:

mg: milligram, g: gram, μl: microliter, ml: milliliter, L: liter, andMHz: megahertz.

In the Examples below, nuclear magnetic resonance (hereinafter, referredto as ¹H NMR; 400 MHz) spectra were indicated by chemical shift δ values(ppm) using tetramethylsilane as a standard. Fragmentation patterns wereindicated by s for a singlet, d for a doublet, t for a triplet, q for aquadruplet, m for a multiplet, and br for broad.

Reference Example 1 tert-Butyl(2S)-2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]pyrrolidine-1-carboxylate

Step 1 tert-Butyl(2S)-2-[(4-bromophenoxy)methyl]pyrrolidine-1-carboxylate

To a solution of 4-bromophenol (1.73 g) and tert-butyl(2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (4.0 g) intetrahydrofuran (50 ml), triphenylphosphine (3.1 g) and a solution ofdiisopropyl azodicarboxylate (2.4 g) in tetrahydrofuran (10 ml) wereadded, and the mixture was heated to reflux for 2 hours. After cooling,the reaction solution was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane-ethyl acetate) to obtain the title compound (3.5 g).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 1.81-2.06 (4H, m), 3.27-3.46 (2H, m),3.70-3.94 (1H, m), 4.03-4.17 (2H, m), 6.81 (2H, br s), 7.35 (2H, d,J=8.7 Hz).

Step 2 tert-Butyl(2S)-2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]pyrrolidine-1-carboxylate

To a solution of the compound (3.5 g) obtained in the preceding step 1in 1,4-dioxane (30 ml), bis(pinacolato)diborane (3.0 g), potassiumacetate (2.9 g), and a[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethaneadduct (0.8 g) were added, and the mixture was stirred at 80° C. for 4hours under a nitrogen atmosphere. After cooling, ethyl acetate wasadded to the reaction solution, and the insoluble matter was filteredoff. The filtrate was concentrated under reduced pressure. Then, theobtained residue was purified by silica gel column chromatography(n-hexane-ethyl acetate) to obtain the title compound (3.4 g).

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.47 (9H, s), 1.79-2.08 (4H, m), 3.40(2H, br s), 3.75-4.20 (3H, m), 6.91 (2H, d, J=7.8 Hz), 7.73 (2H, d,J=8.3 Hz).

The following compounds were obtained by the same procedures as inReference Example 1.

TABLE 1-1 Reference Example Structure and name Instrumental data 2

¹H-NMR (CDCl₃) δ: 1.34 (12H, s), 1.47 (9H, s), 1.79-2.08 (4H, m), 3.41(2H, br s), 3.75-4.21 (3H, m), 7.02 (1H, d, J = 8.3 Hz), 7.27-7.40 (3H,m). 3

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.45 (9H, br s), 2.06-2.21 (2H, m),3.41-3.67 (4H, m), 4.93 (1H, br s), 6.86 (2H, d, J = 8.6 Hz), 7.74 (2H,br s). 4

¹H-NMR (CDCl₃) δ: 1.34 (12H, s), 1.47 (9H, s), 2.04-2.20 (2H, m),3.45-3.65 (4H, m), 4.95 (1H, br s), 6.97 (1H, d, J = 9.2 Hz), 7.25-7.32(2H, m), 7.41 (1H, br s). 5

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.46 (9H, s), 1.72-2.13 (2H, m),2.61-2.73 (1H, m), 3.13-3.65 (4H, m), 3.86-4.01 (2H, m), 6.88 (2H, d, J= 7.8 Hz), 7.74 (2H, d, J = 8.3 Hz). 6

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.47 (9H, s), 1.79-2.08 (4H, m), 3.40(2H, br s), 3.75-4.20 (3H, m), 6.91 (2H, d, J = 7.8 Hz), 7.73 (2H, d, J= 8.3 Hz).

TABLE 1-2  7

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.45 (9H, s), 3.54 (2H, q, J = 5.0 Hz),4.04 (2H, t, J = 5.0 Hz), 4.99 (1H, s), 6.88 (2H, d, J = 9.0 Hz), 7.74(2H, d, J = 9.0 Hz).  8

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.47 (9H, s), 1.71-1.81 (2H, m),1.87-1.96 (2H, m), 3.31-3.39 (2H, m), 3.64-3.72 (2H, m), 4.51-4.57 (1H,m), 6.90 (2H, d, J = 8.3 Hz), 7.74 (2H, d, J = 7.8 Hz).  9

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.44 (9H, s) , 1.95-2.01 (2H, m), 3.33(2H, q, J = 6.3 Hz), 4.05 (2H, t, J = 6.1 Hz), 4.75 (1H, br s), 6.88(2H, d, J = 8.6 Hz), 7.74 (2H, d, J = 8.6 Hz). 10

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.46 (9H, s), 2.98 (3H, s), 3.60 (2H,br s), 4.11 (2H, br s), 6.88 (2H, d, J = 8.6 Hz), 7.74 (2H, d, J = 8.6Hz). 11

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.43 (9H, s), 1.99-2.01 (2H, br m),2.87 (3H, s), 3.40 (2H, t, J = 6.8 Hz), 4.00 (2H, t, J = 6.3 Hz), 6.88(2H, d, J = 8.6 Hz), 7.74 (2H, d, J = 8.6 Hz). 12

¹H-NMR (CDCl₃) δ: 1.29 (3H, d, J = 7.0 Hz), 1.33 (12H, s), 1.45 (9H, s),3.95 (2H, d, J = 3.9 Hz), 4.06 (1H, br s), 4.79 (1H, br s), 6.89 (2H, d,J = 8.6 Hz), 7.74 (2H, d, J = 8.6 Hz).

TABLE 1-3 13

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.46 (9H, s), 1.54-2.11 (6H, m), 4.10(1H, br s), 4.67 (1H, br s), 5.03 (1H, d, J = 8.5 Hz), 6.88 (2H, d, J =8.5 Hz), 7.73 (2H, d, J = 8.5 Hz). 14

¹H-NMR (CDCl₃) δ: 1.21-2.10 (6H, m), 1.33 (12H, s), 1.42 (9H, s), 4.07(1H, br s), 4.65-4.68 (1H, m), 5.03 (1H, d, J = 8.5 Hz), 6.87 (2H, d, J= 8.5 Hz), 7.73 (2H, d, J = 8.5 Hz). 15

¹H-NMR (CDCl₃) δ: 1.29 (3H, d, J = 6.7 Hz), 1.33 (12H, s), 1.45 (9H, s),3.94 (2H, d, J = 3.6 Hz), 4.06 (1H, br s), 4.78 (1H, br s), 6.89 (2H, d,J = 8.5 Hz), 7.74 (2H, d, J = 8.5 Hz). 16

¹H-NMR (CDCl₃) δ: 1.29 (3H, d, J = 7.2 Hz), 1.33 (12H, s), 1.45 (9H, s),3.95 (2H, d, J = 4.2 Hz), 4.06 (1H, br s), 4.77 (1H, br s), 6.89 (2H, d,J = 9.1 Hz), 7.74 (2H, d, J = 9.1 Hz). 17

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.46 (9H, s), 3.50 (2H, br s), 3.65(2H, br s), 3.78 (2H, br s), 4.11-4.22 (2H, m), 6.89 (2H, d, J = 8.5Hz), 7.75 (2H, d, J = 8.5 Hz). 18

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.46 (9H, s), 3.78-4.19 (5H, m), 5.16(1H, br s), 6.90 (2H, d, J = 8.8 Hz), 7.75 (2H, d, J = 8.8 Hz).

TABLE 1-4 19

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.43 (9H, s), 2.94 (3H, s), 3.59 (2H,s), 4.46 (2H, s), 6.69 (1H, d, J = 8.5 Hz), 7.92 (1H, dd, J = 8.5, 2.1Hz), 8.51 (1H, d, J = 2.1 Hz). tert-ButylN-methyl-N-[2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxy]ethyl]carbamate 20

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.46 (9H, br s), 1.83-2.17 (4H, m),3.32-3.47 (2H, m), 3.94 4.26 (3H, m), 7.06 (1H, d, J = 9.1 Hz), 7.92(1H, dd, J = 8.8, 1.5 Hz), 7.99 (1H, s). tert-Butyl(2S)-2-[[2-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]pyrrolidine-1- carboxylate 21

¹H-NMR (CDCl₃) δ: 0.97 (3H, t, J = 7.6 Hz), 1.33 (12H, s), 1.45 (9H, s),1.61-1.76 (2H, m), 3.84 (1H, br s), 3.99 (2H, d, J = 3.6 Hz), 4.77 (1H,d, J = 6.7 Hz), 6.88 (2H, d, J = 8.5 Hz), 7.74 (2H, d, J = 8.5 Hz).tert-Butyl N-[(1S)-1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]propyl]carbamate 22

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.45 (9H, s), 2.35-2.41 (2H, m),2.53-2.59 (2H, m), 4.28 (1H, br s), 4.72-4.85 (2H, m), 6.76 (2H, d, J =9.1 Hz), 7.72 (2H, d, J = 8.5 Hz). tert-ButylN-[3-trans-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]cyclobutyl]carbamate 23

¹H-NMR (CDCl₃) δ: 0.97 (3H, t, J = 7.6 Hz), 1.33 (12H, s), 1.45 (9H, s),1.61-1.76 (2H, m), 3.84 (1H, br s), 3.99 (2H, d, J = 3.6 Hz), 4.77 (1H,d, J = 6.7 Hz), 6.88 (2H, d, J = 8.5 Hz), 7.74 (2H, d, J = 8.5 Hz).tert-Butyl N-[(1R)-1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]propyl]carbamate 24

¹H-NMR (CDCl₃) δ: 1.29 (3H, d, J = 6.7 Hz), 1.34 (12H, s), 1.45 (9H, s),3.91-4.08 (3H, m), 4.80 (1H, br s), 6.99- 7.01 (1H, m), 7.27-7.33 (2H,m), 7.40 (1H, d, J = 7.3 Hz). tert-ButylN-[(1S)-1-methyl-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]carbamate

Reference Example 25 tert-Butyl4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]piperidine-1-carboxylate

Step 1 tert-Butyl 4-(methylsulfonyloxymethyl)piperidine-1-carboxylate

To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate(2.5 g) in dichloromethane (40 ml), triethylamine (2.8 ml) andmethanesulfonyl chloride (1.2 ml) were added under ice cooling, and themixture was stirred at room temperature for 3 hours. Water was added tothe reaction solution to separate two layers. Then, the aqueous layerwas subjected to extraction with chloroform. The organic layers werecombined, washed with saturated saline and then dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure.The obtained residue was purified by silica gel column chromatography(n-hexane-ethyl acetate) to obtain the title compound (2.8 g).

¹H-NMR (CDCl₃) δ: 1.16-1.29 (2H, m), 1.46 (9H, s), 1.74 (2H, d, J=12.8Hz), 1.86-1.97 (1H, m), 2.71 (2H, t, J=12.4 Hz), 3.02 (3H, s), 4.07 (2H,d, J=6.4 Hz), 4.05-4.22 (2H, m).

Step 2 tert-Butyl 4-[(4-bromophenoxy)methyl]piperidine-1-carboxylate

To a solution of the compound (1.9 g) obtained in the preceding step 1in N,N-dimethylformamide (30 ml), sodium iodide (0.97 g), cesiumcarbonate (4.2 g), and 4-bromophenol (0.75 g) were added, and themixture was stirred at 70° C. for 2 hours. After cooling, water wasadded to the reaction solution, followed by extraction with ethylacetate. The extract was washed with water and saturated saline in thisorder and then dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (n-hexane-ethyl acetate) to obtain acrude product of the title compound. The crude product of the titlecompound was dissolved in ethyl acetate. The organic layer was washedwith a 1 N aqueous sodium hydroxide solution and saturated saline inthis order and then dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure to obtain the title compound (0.7g).

¹H-NMR (CDCl₃) δ: 1.20-1.32 (2H, m), 1.46 (9H, s), 1.80 (2H, d, J=13.3Hz), 1.89-1.98 (1H, m), 2.74 (2H, t, J=11.7 Hz), 3.76 (2H, d, J=6.4 Hz),4.15 (2H, br s), 6.76 (2H, d, J=8.3 Hz), 7.36 (2H, d, J=8.7 Hz).

Step 3 tert-Butyl4-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]piperidine-1-carboxylate

The title compound (0.9 g) was obtained by the same procedures as instep 2 of Reference Example 1 using the compound (0.7 g) obtained in thepreceding step 2.

¹H-NMR (CDCl₃) δ: 1.21-1.30 (2H, m), 1.33 (12H, s), 1.46 (9H, s),1.78-1.99 (3H, m), 2.68-2.80 (2H, m), 3.83 (2H, d, J=6.4 Hz), 4.08-4.23(2H, m), 6.87 (2H, d, J=7.8 Hz), 7.74 (2H, d, J=7.8 Hz).

The following compounds were obtained by the same procedures as inReference Example 25.

TABLE 2-1 Reference Example Structure and name Instrumental data 26

¹H-NMR (CDCl₃) δ: 1.31 (12H, s), 1.38 (9H, s), 2.19-2.35 (2H, m),3.81-3.90 (2H, m), 4.08- 4.13 (1H, m), 4.20-4.28 (1H, br m), 4.43-4.51(1H, br m), 6.90 (2H, d, J = 8.6 Hz), 7.71 (2H, d, J= 8.6 Hz).tert-Butyl (2S)-2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]azetidine-1- carboxylate 27

¹H-NMR (CDCl₃) δ: 1.29 (12H, s), 1.41 (9H, s), 3.94-3.98 (2H, m),4.24-4.29 (2H, m), 4.84- 4.91 (1H, m), 6.69 (2H, d, J = 8.6 Hz), 7.71(2H, d, J = 8.6 Hz). tert-Butyl3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]azetidine-1-carboxylate 28

¹H-NMR (CDCl₃) δ: 1.30 (12H, s), 1.41 (9H, s), 2.89-2.98 (1H, m), 3.76(2H, dd, J = 9.0, 4.7 Hz), 4.02-4.12 (4H, m), 6.86 (2H, d, J = 8.9 Hz),7.72 (2H, d, J = 8.9 Hz). tert-Butyl3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]azetidine-1-carboxylate 29

¹H-NMR (CDCl₃) δ: 1.35 (12H, s), 1.42 (9H, s), 2.20-2.39 (2H, m), 3.88(2H, t, J = 7.9 Hz), 4.07-4.15 (1H, m), 4.27 (1H, br s), 4.46-4.53 (1H,m), 6.61 (1H, dd, J = 10.9, 2.4 Hz), 6.72 (1H, dd, J = 8.5, 3.0 Hz),7.65 (1H, t, J = 7.6 Hz). tert-Butyl(2S)-2-[[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]azetidine-1- carboxylate 30

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.41 (9H, s), 2.31-2.38 (2H, m),3.86-3.93 (2H, m), 4.19 (1H, dd, J = 10.0, 2.7 Hz), 4.37 (1H, s), 4.49-4.53 (1H, m), 7.00 (1H, t, J = 8.2 Hz), 7.47-7.53 (2H, m). tert-Butyl(2S)-2-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]azetidine-1- carboxylate

TABLE 2-2 31

¹H-NMR (CDCl₃) δ: 1.34 (12H, s), 1.42 (9H, s), 2.26-2.37 (2H, m),3.85-3.94 (2H, m), 4.11- 4.15 (1H, m), 4.28 (1H, br s), 4.49 (1H, br s),7.04 (1H, dd, J = 8.5, 2.4 Hz), 7.27-7.31 (1H, m), 7.37-7.40 (2H, m).tert-Butyl (2S)-2-[[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]azetidine-1- carboxylate 32

¹H-NMR (CDCl₃) δ: 1.34 (12H, s), 1.42 (9H, s), 2.21-2.37 (2H, m),3.85-3.91 (2H, m), 4.10 (1H, dd, J = 10.0, 2.7 Hz), 4.28 (1H, br s),4.47-4.50 (1H, m), 6.73- 6.76 (1H, m), 7.09 (1H, dd, J = 8.5, 1.8 Hz),7.15 (1H, d, J = 1.8 Hz). tert-Butyl(2S)-2-[[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]azetidine-1- carboxylate 33

¹H-NMR (CDCl₃) δ: 1.34 (12H, s), 1.42 (9H, s), 2.26-2.40 (2H, m),3.85-3.96 (2H, m), 4.20 (1H, dd, J = 9.7, 3.0 Hz), 4.36-4.40 (1H, br m),4.50-4.54 (1H, br m), 7.06 (1H, dd, J = 11.5, 7.9 Hz), 7.36-7.44 (2H,m). tert-Butyl (2S)-2-[[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]azetidine-1- carboxylate

Reference Example 34 tert-ButylN-[cis-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]cyclopentyl]carbamate

Step 1 tert-Butyl N-(trans-2-hydroxycyclopentyl)carbamate

To a tetrahydrofuran-water mixed solution of trans-2-aminocyclopentanolhydrochloride (5.0 g), di-tert-butyl dicarbonate (7.92 g) and potassiumcarbonate (10 g) were added, and the mixture was stirred at roomtemperature for 45 minutes. Water was added to the obtained reactionsolution, followed by extraction with ethyl acetate. The extract waswashed with water and saturated saline in this order and then dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure. The obtained residue was washed with n-hexane-ethyl acetate toobtain the title compound (7.21 g).

¹H-NMR (CDCl₃) δ: 1.28-1.40 (2H, m), 1.45 (9H, s), 1.59-1.81 (2H, m),2.00-2.12 (2H, m), 3.59-3.66 (1H, m), 3.98 (1H, q, J=6.5 Hz), 4.04 (1H,s), 4.70 (1H, br s).

Step 2 tert-Butyl N-[cis-2-(4-bromophenoxy)cyclopentyl]carbamate

The title compound (1.35 g) was obtained by the same procedures as instep 1 of Reference Example 1 with 4-bromophenol as the startingmaterial using the compound (3.37 g) obtained in the preceding step 1instead of tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate.

¹H-NMR (CDCl₃) δ: 1.18-2.11 (6H, m), 1.46 (9H, s), 4.06 (1H, br s), 4.58(1H, t, J=4.5 Hz), 4.97 (1H, d, J=8.6 Hz), 6.77 (2H, d, J=8.6 Hz), 7.36(2H, d, J=8.6 Hz).

Step 3 tert-ButylN-[cis-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]cyclopentyl]carbamate

The title compound (1.18 g) was obtained by the same procedures as instep 2 of Reference Example 1 using the compound (1.35 g) obtained inthe preceding step 2.

¹H-NMR (CDCl₃) δ: 1.17-2.08 (6H, m), 1.26 (12H, s), 1.42 (9H, s), 4.10(1H, br s), 4.66-4.67 (1H, m), 5.03 (1H, d, J=8.6 Hz), 6.87 (2H, d,J=8.6 Hz), 7.73 (2H, d, J=8.6 Hz).

The following compound was obtained by the same procedures as inReference Example 34.

TABLE 3 Reference Example Structure and name Instrumental data 35

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.45 (9H, s), 1.48-2.20 (6H, m), 4.03(1H, br s), 4.51 (1H, br s), 4.61 (1H, br s), 6.95 (2H, d, J = 8.9 Hz),7.73 (2H, d, J = 8.9 Hz). tert-ButylN-[trans-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]cyclopentyl]carbamate

Reference Example 36 tert-Butyl(2S,4S)-4-fluoro-2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]pyrrolidine-1-carboxylate

Step 1 tert-Butyl(2S,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate

To a solution of(2S,4S)-1-tert-butoxycarbonyl-4-fluoropyrrolidine-2-carboxylic acid (4.7g) in tetrahydrofuran (40 ml), a borane-tetrahydrofuran complex (0.95 Msolution in tetrahydrofuran, 31.6 ml) was added under ice cooling, andthe mixture was stirred at room temperature for 1 hour. Ice water and asaturated aqueous solution of sodium bicarbonate were added to thereaction solution, followed by extraction with ethyl acetate. Theextract was washed with saturated saline and then dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure.The obtained residue was purified by silica gel column chromatography(n-hexane-ethyl acetate) to obtain the title compound (4.2 g).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 1.91-2.32 (2H, m), 3.44-3.87 (4H, m),4.10-4.25 (1H, m), 5.03-5.23 (1H, m).

Step 2 tert-Butyl(2S,4S)-4-fluoro-2-(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate

The title compound (5.4 g) was obtained by the same procedures as instep 1 of Reference Example 25 with the compound (4.2 g) obtained in thepreceding step 1 as the starting material.

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 2.02-2.44 (2H, m), 3.01 (3H, s),3.44-3.73 (2H, m), 3.98-4.25 (2H, m), 4.45-4.51 (1H, m), 5.22 (1H, d,J=53.2 Hz).

Step 3 tert-Butyl(2S,4S)-2-[(4-bromophenoxy)methyl]-4-fluoropyrrolidine-1-carboxylate

The title compound (2.0 g) was obtained by the same procedures as instep 2 of Reference Example 25 with the compound (5.4 g) obtained in thepreceding step 2 as the starting material.

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 2.05-2.15 (1H, m), 2.38-2.49 (1H, m),3.47-3.83 (3H, m), 4.12-4.35 (2H, m), 5.21 (1H, d, J=52.4 Hz), 6.81 (2H,d, J=7.8 Hz), 7.33 (2H, d, J=8.6 Hz).

Step 4 tert-Butyl(2S,4S)-4-fluoro-2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]pyrrolidine-1-carboxylate

The title compound (1.8 g) was obtained by the same procedures as instep 2 of Reference Example 1 using the compound (1.9 g) obtained in thepreceding step 3.

¹H-NMR (CDCl₃) δ: 1.29 (12H, s), 1.46 (9H, s), 2.00-2.21 (2H, m),2.39-2.53 (1H, m), 3.46-3.92 (2H, m), 4.14-4.42 (2H, m), 5.10-5.30 (1H,m), 6.90 (2H, d, J=8.6 Hz), 7.71 (2H, d, J=7.8 Hz).

Reference Example 37 tert-ButylN-cyclopropyl-N-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]carbamate

Step 1 1-Bromo-4-(2-bromoethoxy)benzene

The title compound (2.7 g) was obtained by the same procedures as instep 1 of Reference Example 1 with 4-bromophenol as the startingmaterial using 2-bromoethanol (1.9 g) instead of tert-butyl(2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate.

¹H-NMR (CDCl₃) δ: 3.63 (2H, t, J=5.4 Hz), 4.26 (2H, t, J=6.0 Hz), 6.80(2H, d, J=9.1 Hz), 7.39 (2H, d, J=9.1 Hz).

Step 2 tert-Butyl N-[2-(4-bromophenoxy)ethyl]-N-cyclopropylcarbamate

To a solution of the compound (2.7 g) obtained in the preceding step 1in N,N-dimethylformamide (20 ml), cyclopropylamine (2.0 ml) was added,and the mixture was stirred at room temperature for 2.5 hours. Water wasadded to the reaction solution, followed by extraction with ethylacetate. The extract was washed with water and saturated saline in thisorder and then dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. The obtained residue was dissolvedin ethanol (30 ml). To this solution, di-tert-butyl dicarbonate (2.2 g)was added, and the mixture was stirred at room temperature for 1.5hours. The reaction solution was concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(n-hexane-ethyl acetate) to obtain the title compound (1.0 g).

¹H-NMR (CDCl₃) δ: 0.62-0.78 (4H, m), 1.46 (9H, s), 2.56-2.63 (1H, m),3.59 (2H, t, J=5.4 Hz), 4.06 (2H, t, J=5.4 Hz), 6.77 (2H, d, J=9.1 Hz),7.36 (2H, d, J=8.5 Hz).

Step 3 tert-ButylN-cyclopropyl-N-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]carbamate

The title compound (1.2 g) was obtained by the same procedures as instep 2 of Reference Example 1 using the compound (1.0 g) obtained in thepreceding step 2.

¹H-NMR (CDCl₃) δ: 0.63-0.78 (4H, m), 1.33 (12H, s), 1.46 (9H, s),2.56-2.65 (1H, m), 3.61 (2H, t, J=6.0 Hz), 4.12 (3H, t, J=6.0 Hz), 6.88(2H, d, J=7.3 Hz), 7.74 (2H, d, J=7.3 Hz).

Reference Example 38 tert-ButylN-methyl-N-[1-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]carbamate

Step 1 tert-ButylN-[2-(4-bromophenoxy)-1-methyl-ethyl]-N-methylcarbamate

To a solution of the compound (3.80 g) obtained in step 1 of ReferenceExample 12 by the same procedures as in step 1 of Reference Example 1 inN,N-dimethylformamide (40 ml), sodium hydride (55% oil, 0.57 g) wasadded, and the mixture was stirred at room temperature for 20 minutes.Then, methyl iodide (2.83 g) was added thereto, and the mixture wasfurther stirred at room temperature for 40 minutes. After ice cooling,water was added to the reaction solution, followed by extraction withethyl acetate. The extract was washed with water and saturated saline inthis order and then dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (n-hexane-ethyl acetate) to obtainthe title compound (3.79 g).

¹H-NMR (CDCl₃) δ: 1.23 (3H, d, J=6.7 Hz), 1.46 (9H, s), 2.79 (3H, s),3.87 (1H, br s), 3.93 (1H, dd, J=9.7, 7.3 Hz), 4.41-4.57 (1H, m), 6.77(2H, d, J=9.1 Hz), 7.36 (2H, d, J=9.1 Hz).

Step 2 tert-ButylN-methyl-N-[1-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]carbamate

The title compound (0.78 g) was obtained by the same procedures as instep 2 of Reference Example 1 using the compound (1.29 g) obtained inthe preceding step 1.

¹H-NMR (CDCl₃) δ: 1.24 (3H, d, J=6.8 Hz), 1.33 (12H, s), 1.46 (9H, s),2.80 (3H, s), 3.93 (1H, br s), 3.99 (1H, dd, J=9.7, 6.7 Hz), 4.44-4.59(1H, m), 6.87 (2H, d, J=8.5 Hz), 7.73 (2H, d, J=8.5 Hz).

Reference Example 39 tert-ButylN-[1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]cyclopropyl]carbamate

Step 1 tert-Butyl N-[1-(hydroxymethyl)cyclopropyl]carbamate

A solution of 1-(N-tert-butoxycarbonylamino)cyclopropanecarboxylic acid(5 g) in tetrahydrofuran was cooled to −20° C. Isobutyl chloroformate(3.24 ml) and N-methylmorpholine (2.74 ml) were added thereto, and themixture was stirred at the same temperature as above for 20 minutes.Then, sodium borohydride (1.12 g) and water (1 ml) were added thereto,and the mixture was further stirred at room temperature for 40 minutes.Water was added to the reaction solution, followed by extraction withethyl acetate. The extract was washed with water and saturated saline inthis order and then dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (n-hexane-ethyl acetate) to obtainthe title compound (4.24 g).

¹H-NMR (CDCl₃) δ: 0.81-0.85 (4H, m), 1.44 (9H, s), 3.43 (1H, br s), 3.59(2H, d, J=4.8 Hz), 5.07 (1H, br s).

Step 2 [1-(tert-Butoxycarbonylamino)cyclopropyl]methyl methanesulfonate

The title compound (3.93 g) was obtained by the same procedures as instep 1 of Reference Example 25 using the compound (3.21 g) obtained inthe preceding step 1.

¹H-NMR (CDCl₃) δ: 0.92-0.96 (4H, m), 1.44 (9H, s), 3.03 (3H, s), 4.25(2H, s), 5.06 (1H, br s).

Step 3 tert-Butyl N-[1-[(4-bromophenoxy)methyl]cyclopropyl]carbamate

The title compound (0.43 g) was obtained by the same procedures as instep 2 of Reference Example 25 using the compound (2.05 g) obtained inthe preceding step 2.

¹H-NMR (CDCl₃) δ: 0.89-0.92 (4H, m), 1.43 (9H, s), 3.94 (2H, s), 5.11(1H, br s), 6.77 (2H, d, J=9.1 Hz), 7.36 (2H, d, J=9.1 Hz).

Step 4 tert-ButylN-[1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]cyclopropyl]carbamate

The title compound (0.39 g) was obtained by the same procedures as instep 2 of Reference Example 1 using the compound (0.43 g) obtained inthe preceding step 3.

¹H-NMR (CDCl₃) δ: 0.89-0.92 (4H, m), 1.33 (12H, s), 1.42 (9H, s), 3.99(2H, s), 5.14 (1H, br s), 6.88 (2H, d, J=8.5 Hz), 7.73 (2H, d, J=8.5Hz).

Reference Example 40 tert-Butyl(2S,4S)-4-fluoro-2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxymethyl]pyrrolidine-1-carboxylate

Step 1 tert-Butyl(2S,4S)-4-fluoro-2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxymethyl]pyrrolidine-1-carboxylate

The title compound (1.0 g) was obtained by the same procedures as instep 1 of Reference Example 1 with the compound (1.25 g) obtained instep 1 of Reference Example 36 as the starting material using5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol (1.26 g)instead of 4-bromophenol.

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.47 (9H, s), 2.06-2.24 (1H, m), 2.45(1H, dd, J=20.0, 14.5 Hz), 3.66-3.74 (2H, m), 4.18 (1H, br s), 4.32 (1H,br s), 4.66 (1H, br s), 5.23 (1H, d, J=52.6 Hz), 6.71 (1H, d, J=8.5 Hz),7.92 (1H, dd, J=8.5, 1.2 Hz), 8.52 (1H, d, J=1.2 Hz).

The following compounds were obtained by the same procedures as inReference Example 40.

TABLE 4 Reference Example Structure and name Instrumental data 41

¹H-NMR (CDCl₃) δ: 1.25 (3H, d, J = 7.3 Hz), 1.33 (12H, s), 1.44 (9H, s),4.07 (1H, br s), 4.25- 4.33 (2H, m), 4.87 (1H, br s), 6.72 (1H, d, J =8.2 Hz), 7.93 (1H, dd, J = 8.2, 2.1 Hz), 8.51 (1H, d, J = 2.1 Hz).tert-Butyl N-[(1R)-1-methyl-2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxy]ethyl]carbamate 42

¹H-NMR (CDCl₃) δ: 1.25 (3H, d, J = 7.3 Hz), 1.33 (12H, s), 1.44 (9H, s),4.08 (1H, br s), 4.25- 4.33 (2H, m), 4.93-5.03 (1H, m), 6.72 (1H, d, J =8.2 Hz), 7.93 (1H, dd, J = 8.2, 1.8 Hz), 8.51 (1H, d, J = 1.8 Hz).tert-Butyl N-[(1S)-1-methyl-2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxy]ethyl]carbamate

Reference Example 43 tert-ButylN-[(1R,2R)-2-hydroxy-1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]propyl]carbamate

Step 1 tert-Butyl N-[(1R,2R)-2-hydroxy-1-(hydroxymethyl)propyl]carbamate

The title compound (1.58 g) was obtained by the same procedures as instep 1 of Reference Example 39 with(2S,3R)-2-(tert-butoxycarbonylamino)-3-hydroxybutyric acid (3.42 g) asthe starting material.

¹H-NMR (CDCl₃) δ: 1.23 (3H, d, J=6.7 Hz), 1.46 (9H, s), 2.35 (1H, br s),2.44 (1H, br s), 3.53 (1H, br s), 3.82-3.85 (2H, br m), 4.15 (2H, br s),5.22 (1H, br s).

Step 2 tert-ButylN-[(1R,2R)-1-[(4-bromophenoxy)methyl]-2-hydroxypropyl]carbamate

The title compound (1.09 g) was obtained by the same procedures as instep 1 of Reference Example 1 with 4-bromophenol (0.87 g) as thestarting material using the compound (1.58 g) obtained in the precedingstep 1 instead of tert-butyl(2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate.

¹H-NMR (CDCl₃) δ: 1.27 (3H, d, J=6.7 Hz), 1.46 (9H, s), 2.30 (1H, br s),3.81 (1H, br s), 4.07 (2H, d, J=4.8 Hz), 4.18-4.21 (1H, m), 5.13 (1H, d,J=8.5 Hz), 6.80 (2H, d, J=9.1 Hz), 7.38 (2H, d, J=9.1 Hz).

Step 3 tert-ButylN-[(1R,2R)-2-hydroxy-1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]propyl]carbamate

The title compound (1.07 g) was obtained by the same procedures as instep 2 of Reference Example 1 using the compound (1.09 g) obtained inthe preceding step 2.

¹H-NMR (CDCl₃) δ: 1.26 (3H, d, J=6.7 Hz), 1.33 (12H, s), 1.46 (9H, s),3.83 (1H, br s), 4.14 (2H, br s), 4.21 (1H, br s), 5.18 (1H, d, J=8.5Hz), 6.89 (2H, d, J=8.8 Hz), 7.75 (2H, d, J=8.8 Hz).

Reference Example 44 tert-ButylN-[(1S,2S)-2-hydroxy-1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]propyl]carbamate

Step 1 tert-Butyl N-[(1S,2S)-2-hydroxy-1-(hydroxymethyl)propyl]carbamate

The title compound (2.24 g) was obtained by the same procedures as instep 1 of Reference Example 39 with(2R,3S)-2-(tert-butoxycarbonylamino)-3-hydroxybutyric acid (4.28 g) asthe starting material.

¹H-NMR (CDCl₃) δ: 1.23 (3H, d, J=6.7 Hz), 1.46 (9H, s), 2.41 (1H, br s),2.49 (1H, br s), 3.52 (1H, br s), 3.83 (2H, d, J=3.0 Hz), 4.15 (2H, brs), 5.21 (1H, br s).

Step 2 tert-ButylN-[(1S,2S)-2-hydroxy-1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]propyl]carbamate

The title compound (0.97 g) was obtained by the same procedures as instep 1 of Reference Example 1 with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.54 g) as thestarting material using the compound (2.24 g) obtained in the precedingstep 1 instead of tert-butyl(2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate.

¹H-NMR (CDCl₃) δ: 1.27 (3H, d, J=6.7 Hz), 1.33 (12H, s), 1.46 (9H, s),2.44 (1H, br s), 3.82 (1H, br s), 4.13 (2H, br s), 4.19-4.23 (1H, m),5.18 (1H, d, J=9.1 Hz), 6.90 (2H, d, J=8.5 Hz), 7.75 (2H, d, J=8.5 Hz).

Reference Example 45 tert-ButylN-[(1R)-1-[[tert-butyldimethylsilyl]oxymethyl]-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]carbamate

Step 1 tert-ButylN-[(1R)-1-[[tert-butyldimethylsilyl]oxymethyl]-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]carbamate

The title compound (3.34 g) was obtained by the same procedures as instep 1 of Reference Example 1 with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.86 g) as thestarting material using tert-butylN-[(1R)-1-[[tert-butyldimethylsilyl]oxymethyl]-2-hydroxyethyl]carbamate(5.0 g) instead of tert-butyl(2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate.

¹H-NMR (CDCl₃) δ: 0.02 (6H, s), 0.86 (9H, s), 1.33 (12H, s), 1.46 (9H,s), 3.69 (1H, dd, J=10.3, 5.4 Hz), 3.84 (1H, dd, J=10.3, 3.3 Hz), 3.98(2H, br s), 4.11 (1H, br s), 4.96 (1H, d, J=6.0 Hz), 6.90 (2H, d, J=8.5Hz), 7.73 (2H, d, J=8.5 Hz).

The following compounds were obtained by the same procedures as inReference Example 45.

TABLE 5 Reference Example Structure and name Instrumental data 46

¹H-NMR (CDCl₃) δ: 1.34 (12H, s), 1.46 (9H, s), 2.99 (3H, s), 3.60 (2H,br s), 4.10 (3H, br s), 6.98-7.00 (1H, m), 7.27-7.32 (2H, m), 7.40 (1H,d, J = 7.3 Hz). tert-Butyl N-methyl-N-[2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]carbamate 47

  tert-Butyl N-[(1R)-1-methyl-2-[3-(4,4,5,5-tetramethyl- ¹H-NMR (CDCl₃)δ: 1.29 (3H, d, J = 6.7 Hz), 1.34 (12H, s), 1.45 (9H, s), 3.95-3.97 (2H,m), 4.05 (1H, br s), 4.80 (1H, br s), 6.99-7.01 (1H, m), 7.28 (1H, d, J= 7.3 Hz), 7.32-7.32 (1H, m), 7.40 (1H, d, J = 6.7 Hz).1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]carbamate 48

¹H-NMR (CDCl₃) δ: 1.34 (12H, s), 1.44 (9H, s), 1.97-2.01 (2H, m), 2.87(3H, s), 3.40 (2H, t, J = 7.0 Hz), 4.00 (2H, t, J = 6.3 Hz), 6.98-7.00(1H, m), 7.29-7.32 (2H, m), 7.39 (1H, d, J = 7.3 Hz). tert-ButylN-methyl-N-[3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propyl]carbamate 49

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.45 (9H, s), 3.53 (2H, q, J = 5.0 Hz),4.05 (2H, t, J = 5.1 Hz), 4.99 (1H, br s), 6.93-7.01 (1H, m), 7.22- 7.32(2H, m), 7.39 (1H, dd, J = 14.5, 7.3 Hz). tert-ButylN-[2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]carbamate 50

¹H-NMR (CDCl₃) δ: 1.34 (12H, s), 1.44 (9H, s), 1.94-2.00 (2H, m), 3.32(2H, q, J = 6.3 Hz), 4.06 (2H, t, J = 5.7 Hz), 4.77 (1H, br s), 6.99-7.01 (1H, m), 7.27-7.33 (2H, m), 7.40 (1H, d, J = 7.3 Hz). tert-ButylN-[3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propyl]carbamate

Reference Example 51 tert-Butyl(2S)-2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfanylmethyl]pyrrolidine-1-carboxylate

Step 1 tert-Butyl(2S)-2-(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate

The title compound (1.4 g) was obtained by the same procedures as instep 1 of Reference Example 25 with tert-butyl(2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.0 g) as the startingmaterial.

¹H-NMR (CDCl₃) δ: 1.46 (9H, br s), 1.79-2.09 (4H, m), 3.01 (3H, s),3.31-3.46 (2H, m), 3.96-4.36 (3H, m).

Step 2 tert-Butyl(2S)-2-[(4-bromophenyl)sulfanylmethyl]pyrrolidine-1-carboxylate

To a solution of the compound (1.4 g) obtained in the preceding step 1in N,N-dimethylformamide (20 ml), potassium carbonate (1.1 g) and4-bromobenzenethiol (0.76 g) were added, and the mixture was stirred atroom temperature for 19 hours. Water was added to the reaction solution,followed by extraction with ethyl acetate. The extract was washed withwater and saturated saline in this order and then dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure.The obtained residue was purified by silica gel column chromatography(n-hexane-ethyl acetate) to obtain the title compound (0.9 g).

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.76-2.05 (4H, m), 2.61-2.83 (1H, m),3.28-3.51 (3H, m), 3.87-4.06 (1H, m), 7.31 (2H, d, J=7.9 Hz), 7.39 (2H,d, J=8.5 Hz).

Step 3 tert-Butyl(2S)-2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfanylmethyl]pyrrolidine-1-carboxylate

The title compound (0.7 g) was obtained by the same procedures as instep 2 of Reference Example 1 using the compound (0.9 g) obtained in thepreceding step 2.

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.45 (9H, br s), 1.75-2.04 (4H, m),2.61-2.87 (1H, m), 3.28-3.56 (3H, m), 3.90-4.08 (1H, m), 7.35 (2H, d,J=7.9 Hz), 7.69 (2H, d, J=7.9 Hz).

Reference Example 52(2R)-3-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2-(tritylamino)propan-1-ol

Step 1 Methyl (2S)-3-(4-bromophenoxy)-2-(tritylamino)propanoate

The title compound (4.80 g) was obtained by the same procedures as instep 1 of Reference Example 1 with 4-bromophenol (3.46 g) as thestarting material using methyl (2S)-3-hydroxy-2-(tritylamino)propanoate(7.26 g) instead of tert-butyl(2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate.

¹H-NMR (CDCl₃) δ: 2.87 (1H, d, J=10.3 Hz), 3.23 (3H, s), 3.68-3.74 (1H,m), 3.97 (1H, dd, J=9.7, 6.7 Hz), 4.20 (1H, dd, J=9.7, 4.8 Hz), 6.75(2H, d, J=9.1 Hz), 7.16-7.55 (17H, m).

Step 2 (2R)-3-(4-Bromophenoxy)-2-(tritylamino)propan-1-ol

To a solution of the compound (4.80 g) obtained in the preceding step 1in tetrahydrofuran (50 ml), lithium aluminum hydride (189 mg) was addedunder ice cooling, and the mixture was stirred at 0° C. for 2 hours.Water was added to the reaction solution to separate two layers. Then,the aqueous layer was subjected to extraction with ethyl acetate. Theorganic layers were combined, washed with saturated saline and thendried over anhydrous magnesium sulfate. The solvent was distilled offunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (n-hexane-ethyl acetate) to obtain the titlecompound (4.14 g).

¹H-NMR (CDCl₃) δ: 1.79 (1H, t, J=5.7 Hz), 2.42 (1H, br s), 3.02-3.12(3H, m), 3.55-3.62 (2H, m), 6.55 (2H, d, J=9.1 Hz), 7.17-7.59 (17H, m).

Step 3(2R)-3-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-2-(tritylamino)propan-1-ol

The title compound (1.08 g) was obtained by the same procedures as instep 2 of Reference Example 1 using the compound (1.18 g) obtained inthe preceding step 2.

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.83 (1H, br s), 2.46 (1H, br s), 3.06(2H, br s), 3.17 (1H, dd, J=9.4, 6.0 Hz), 3.58-3.61 (1H, m), 3.65 (1H,dd, J=9.4, 3.3 Hz), 6.67 (2H, d, J=8.8 Hz), 7.18-7.20 (3H, m), 7.22-7.30(6H, m), 7.52-7.62 (6H, m), 7.67 (2H, d, J=8.8 Hz).

Reference Example 53 tert-ButylN-[3-cis-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]cyclobutyl]carbamate

Step 1 Benzyl 3-cis-formyloxycyclobutanecarboxylate

To a solution of benzyl 3-cis-hydroxycyclobutanecarboxylate (7.40 g) andformic acid (1.62 ml) in tetrahydrofuran (80 ml), triphenylphosphine(11.28 g) and a solution of diethyl azodicarboxylate in toluene (40%,19.5 ml) were added, and the mixture was stirred at room temperature for2 hours. The reaction solution was concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(n-hexane-ethyl acetate) to obtain the title compound (8.59 g).

¹H-NMR (CDCl₃) δ: 2.38-2.46 (2H, m), 2.69-2.75 (2H, m), 3.17-3.24 (1H,m), 5.15 (2H, s), 5.30-5.33 (1H, m), 7.32-7.40 (5H, m), 7.97 (1H, s).

Step 2 Benzyl 3-trans-hydroxycyclobutanecarboxylate

To the compound (8.59 g) obtained in the preceding step 1, dimethylamine(2 M solution in tetrahydrofuran, 50 ml) was added, and the mixture wasstirred at room temperature for 5 hours. The reaction solution wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (n-hexane-ethyl acetate) to obtainthe title compound (5.36 g).

¹H-NMR (CDCl₃) δ: 1.81 (1H, d, J=5.4 Hz), 2.19-2.27 (2H, m), 2.56-2.63(2H, m), 3.05-3.11 (1H, m), 4.55-4.60 (1H, m), 5.13 (2H, s), 7.30-7.39(5H, m).

Step 3 Benzyl 3-cis-(4-bromophenoxy)cyclobutanecarboxylate

The title compound (6.03 g) was obtained by the same procedures as instep 1 of Reference Example 1 with 4-bromophenol (4.84 g) as thestarting material using the compound (5.36 g) obtained in the precedingstep 2 instead of tert-butyl(2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate.

¹H-NMR (CDCl₃) δ: 2.41-2.50 (2H, m), 2.69-2.77 (2H, m), 2.81-2.88 (1H,m), 4.50-4.58 (1H, m), 5.14 (2H, s), 6.68 (2H, d, J=9.1 Hz), 7.30-7.39(7H, m).

Step 4 3-cis-(4-Bromophenoxy)cyclobutanecarboxylic acid

To a solution of the compound (6.03 g) obtained in the preceding step 3in ethanol (40 ml), a 1 N aqueous sodium hydroxide solution (40 ml) wasadded, and the mixture was stirred at room temperature for 2.5 hours. 1N hydrochloric acid (60 ml) was added to the reaction solution. Theaqueous layer was subjected to extraction with ethyl acetate. Theorganic layers were combined, washed with saturated saline and thendried over anhydrous magnesium sulfate. The solvent was distilled offunder reduced pressure to obtain the title compound (4.30 g).

¹H-NMR (CDCl₃) δ: 2.43-2.52 (2H, m), 2.73-2.80 (2H, m), 2.84-2.89 (1H,m), 4.53-4.60 (1H, m), 6.68 (2H, d, J=8.8 Hz), 7.36 (2H, d, J=8.8 Hz).

Step 5 tert-Butyl N-[3-cis-(4-bromophenoxy)cyclobutyl]carbamate

To a solution of the compound (4.3 g) obtained in the preceding step 4in toluene (50 ml), triethylamine (2.40 g) and diphenylphosphoryl azide(4.09 ml) were added, and the mixture was heated at 90° C. for 1 hour.Tert-butanol (15 ml) was added to the mixture, and the resulting mixturewas further stirred at the same temperature as above for 3 hours. Aftercooling, ethyl acetate was added to the reaction solution. The organiclayer was washed with water and saturated saline in this order and driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure. The obtained residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate) to obtain the title compound(2.11 g).

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 1.95-2.05 (2H, m), 2.91-2.96 (2H, m),3.91 (1H, br s), 4.29-4.36 (1H, m), 4.68 (1H, br s), 6.67 (2H, d, J=9.1Hz), 7.35 (2H, d, J=9.1 Hz).

Step 6 tert-ButylN-[3-cis-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]cyclobutyl]carbamate

The title compound (0.84 g) was obtained by the same procedures as instep 2 of Reference Example 1 using the compound (0.85 g) obtained inthe preceding step 5.

¹H-NMR (CDCl₃) δ: 1.32 (12H, s), 1.44 (9H, s), 1.95-2.03 (2H, m), 2.95(2H, br s), 3.91 (1H, br s), 4.38-4.45 (1H, m), 4.67-4.69 (1H, br m),6.78 (2H, d, J=8.9 Hz), 7.72 (2H, d, J=8.9 Hz).

Reference Example 54 (+)-1-(2,5-Difluoro-3-pyridyl)ethanol

Step 1 2,5-Difluoro-N-methoxy-N-methylpyridine-3-carboxamide

To a solution of 2,5-difluoropyridine-3-carboxylic acid (3.00 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.34 g),1-hydroxybenzotriazole (127 mg), and N,O-dimethylhydroxylaminehydrochloride (1.93 g) in N,N-dimethylformamide (30 ml),diisopropylethylamine (7.42 ml) was added, and the mixture was stirredovernight at room temperature. Ethyl acetate and water were added to thereaction solution to separate the aqueous and organic layers. Theaqueous layer was subjected to extraction with ethyl acetate. Theorganic layers were combined, washed with saturated saline, dried overanhydrous sodium sulfate and then concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(hexane-ethyl acetate) to obtain the title compound (2.42 g).

¹H-NMR (CDCl₃) δ: 3.37 (3H, s), 3.59 (3H, s), 7.64 (1H, td, J=6.7, 3.0Hz), 8.11-8.13 (1H, m).

ESI-MS (m/z): 203 (M+H)⁺.

Step 2 1-(2,5-Difluoro-3-pyridyl)ethanone

The compound (2.40 g) obtained in the preceding step 1 was dissolved intetrahydrofuran (50 ml). To the solution, methyl magnesium bromide (1 Msolution in tetrahydrofuran, 17.8 ml) was added under ice cooling, andthe mixture was then stirred at room temperature for 45 minutes. Methylmagnesium bromide (1 M solution in tetrahydrofuran, 5.9 ml) was furtheradded thereto, and the mixture was stirred at room temperature for 30minutes, followed by addition of a saturated aqueous solution ofammonium chloride. Ethyl acetate was added to the reaction solution toseparate the aqueous and organic layers. The organic layer was driedover anhydrous sodium sulfate and then concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate) to obtain the title compound(1.36 g).

¹H-NMR (CDCl₃) δ: 2.70 (3H, d, J=4.8 Hz), 8.05 (1H, td, J=7.3, 3.9 Hz),8.22-8.24 (1H, m).

Step 3 1-(2,5-Difluoro-3-pyridyl)ethanol

(+)-B-Chlorodiisopinocampheylborane (1.6 M solution in n-hexane, 7.7 ml)was diluted with tetrahydrofuran (25 ml). To the dilution, a solution ofthe compound (878 mg) obtained in the preceding step 2 intetrahydrofuran (10 ml) was added under ice cooling. After stirring at0° C. for 5 hours, the solvent was distilled off under reduced pressure,and diethyl ether (100 ml) was added to the residue. Diethanolamine(1.29 g) was added thereto, and the mixture was stirred at roomtemperature for 2.5 hours. The deposited solid was collected byfiltration. The obtained solid was dissolved in water, followed byextraction with ethyl acetate. The extract and the filtrate werecombined, dried over anhydrous sodium sulfate and then concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (n-hexane-ethyl acetate; and subsequently basicsilica gel, n-hexane-ethyl acetate) to obtain the title compound (647mg).

¹H-NMR (CDCl₃) δ: 1.53 (3H, d, J=6.7 Hz), 2.03 (1H, d, J=4.2 Hz),5.09-5.15 (1H, m), 7.73 (1H, td, J=7.9, 3.0 Hz), 7.91-7.93 (1H, m).

Step 43-[1-[[(3a5,6aS)-3a-Allyl-3,4,5,6-tetrahydro-2H-cyclopenta[b]furan-6a-yl]oxy]ethyl]-2,5-difluoropyridine

The compound (644 mg) obtained in the preceding step 3 and(3aS)-3a-allyl-2,3,4,5-tetrahydrocyclopenta[b]furan (730 mg) weredissolved in toluene (20 ml). To the solution, p-toluenesulfonic acidpyridine salt (712 mg) was added, and the mixture was stirred at roomtemperature for 3 days. Ethyl acetate and a saturated aqueous solutionof sodium bicarbonate were added to the reaction solution to separatethe aqueous and organic layers. The organic layer was dried overanhydrous sodium sulfate and then concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(n-hexane-ethyl acetate) to obtain the title compound (926 mg).

¹H-NMR (CDCl₃) δ: 1.40 (3H, d, J=6.7 Hz), 1.49-1.74 (6H, m), 1.89-1.95(1H, m), 2.19-2.25 (2H, m), 2.33 (1H, dd, J=13.9, 7.9 Hz), 3.33 (1H, q,J=7.9 Hz), 3.64 (1H, td, J=8.5, 4.2 Hz), 5.02-5.15 (3H, m), 5.82-5.92(1H, m), 7.62 (1H, td, J=7.9, 3.0 Hz), 7.88-7.89 (1H, m).

Step 5 (+)-1-(2,5-Difluoro-3-pyridyl)ethanol

The compound (902 mg) obtained in the preceding step 4 was dissolved inmethanol (20 ml). To the solution, p-toluenesulfonic acid monohydrate(55 mg) was added, and the mixture was stirred at 50° C. for 1 hour. Asaturated aqueous solution of sodium bicarbonate and ethyl acetate wereadded to the reaction solution to separate the aqueous and organiclayers. The aqueous layer was subjected to extraction with ethylacetate. The organic layers were combined, dried over anhydrous sodiumsulfate and then concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (n-hexane-ethylacetate) to obtain the title compound (375 mg).

¹H-NMR (CDCl₃) δ: 1.52 (3H, d, J=6.7 Hz), 2.21 (1H, d, J=4.2 Hz),5.08-5.15 (1H, m), 7.73 (1H, td, J=7.9, 3.0 Hz), 7.91-7.92 (1H, m).

[α]_(D)+55.90° (c=0.916, methanol, 25.0° C.)

Reference Example 55 (+)-1-(5-Chloro-1-methylpyrazol-3-yl)ethanol

Step 1 5-Chloro-N-methoxy-N,1-dimethylpyrazole-3-carboxamide

5-Chloro-1-methyl-1H-pyrazole-3-carboxylic acid (982 mg) was added to asolution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(2.39 g), 1-hydroxybenzotriazole (252 mg), and N,O-dimethylhydroxylaminehydrochloride (1.21 g) in dichloromethane (50 ml). Triethylamine (2.4ml) was added dropwise to the mixture, and the resulting mixture wasstirred overnight at room temperature. The reaction solution was dilutedwith dichloromethane (20 ml). Water (50 ml) was added to the dilution toseparate the aqueous and organic layers. The organic layer was washedwith water (50 ml). The organic layer was dried over anhydrous magnesiumsulfate. After filtration, the solvent was distilled off under reducedpressure. The obtained residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate) to obtain the title compound(1.14 g).

¹H-NMR (CDCl₃) δ: 3.37 (3H, s), 3.71-3.71 (3H, m), 3.87-3.88 (3H, m),6.67 (1H, s).

ESI-MS (m/z): 203 (M+H)⁺.

Step 2 1-(5-Chloro-1-methylpyrazol-3-yl)ethanone

A solution of the compound (1.14 g) obtained in the preceding step 1 intetrahydrofuran (15 ml) was cooled in ice, and methyl magnesium bromide(0.99 M solution in tetrahydrofuran, 12.5 ml) was added dropwise theretoover 5 minutes. The reaction solution was stirred for 2 hours under icecooling and then at room temperature for 30 minutes. The reactionsolution was diluted with ethyl acetate (30 ml). After ice cooling, 1 Nhydrochloric acid (6.7 ml) was added dropwise to the reaction solution.Then, a saturated aqueous solution of sodium bicarbonate (12 ml) and anaqueous sodium hydroxide solution (4 ml) were further added to themixture, and the resulting mixture was stirred at room temperature for30 minutes. The insoluble matter was filtered off through celite, andthe filtrate was then separated into the aqueous and organic layers. Theaqueous layer was subjected to extraction with ethyl acetate (20 ml).The organic layer was dried over anhydrous magnesium sulfate. Afterfiltration, the solvent was distilled off under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane-ethyl acetate) to obtain the title compound (752 mg).

¹H-NMR (CDCl₃) δ: 2.50 (3H, s), 3.88 (3H, s), 6.68 (1H, s).

Step 3 1-(5-Chloro-1-methylpyrazol-3-yl)ethanol

A solution of the compound (741 mg) obtained in the preceding step 2 inmethanol (12 ml) was cooled in ice, and sodium borohydride (230 mg) wasadded thereto. The mixture was stirred for 4 hours under ice cooling. Asaturated ammonium chloride solution (0.8 ml) was added dropwise to thereaction solution, and the mixture was stirred for 5 minutes and thenfurther stirred at room temperature for 10 minutes. The solvent wasdistilled off under reduced pressure, and the residue was diluted withethyl acetate (50 ml). A saturated aqueous solution of sodiumbicarbonate (15 ml) was added to the dilution to separate the aqueousand organic layers. The aqueous layer was subjected to extraction withethyl acetate (20 ml). The organic layer was dried over anhydrousmagnesium sulfate. After filtration, the solvent was distilled off underreduced pressure. The obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate) to obtain the title compound(685 mg).

¹H-NMR (CDCl₃) δ: 1.46 (3H, d, J=6.6 Hz), 2.43 (1H, d, J=4.3 Hz), 3.76(3H, s), 4.81-4.83 (1H, m), 6.13 (1H, s).

Step 43-[1-[[(3aR,6aR)-3a-Allyl-3,4,5,6-tetrahydro-2H-cyclopenta[b]furan-6a-yl]oxy]ethyl]-5-chloro-1-methylpyrazole

To a solution of the compound (1.355 g) obtained in the preceding step 3in toluene (36 ml), a solution of(3aR)-3a-allyl-2,3,4,5-tetrahydrocyclopenta[b]furan (1.52 g) in toluene(6 ml) was added. To this solution, p-toluenesulfonic acid pyridine salt(1.48 g) was added, and the mixture was stirred for 3 hours. Thereaction solution was fractionated with ethyl acetate and a saturatedaqueous solution of sodium bicarbonate. The organic layer was washedwith saturated saline and then dried over anhydrous magnesium sulfate.After filtering off the insoluble matter, the solvent in the filtratewas distilled off under reduced pressure. The obtained residue waspurified by silica gel column chromatography (n-hexane-ethyl acetate) toobtain low polar isomer A (1.108 g) and highly polar isomer B (1.017 g).

Low polar isomer A (Rf=0.60, n-hexane:ethyl acetate=3:1)

¹H-NMR (CDCl₃) δ: 1.38-1.59 (5H, m), 1.42 (3H, d, J=6.7 Hz), 1.67-1.74(1H, m), 1.94-2.03 (2H, m), 2.09 (1H, dd, J=13.9, 7.3 Hz), 2.32 (1H, dd,J=13.9, 7.3 Hz), 3.78 (3H, s), 3.81-3.90 (2H, m), 4.89 (1H, q, J=6.7Hz), 5.00-5.10 (2H, m), 5.81-5.91 (1H, m), 6.15 (1H, s).

Highly polar isomer B (Rf=0.51, n-hexane:ethyl acetate=3:1)

¹H-NMR (CDCl₃) δ: 1.42 (3H, d, J=6.7 Hz), 1.48-1.71 (6H, m), 1.88-1.94(1H, m), 2.13 (1H, dd, J=13.9, 7.3 Hz), 2.17-2.22 (1H, m), 2.28 (1H, dd,J=13.9, 7.3 Hz), 3.58 (1H, q, J=7.9 Hz), 3.72 (1H, td, J=7.9, 4.2 Hz),3.78 (3H, s), 4.87 (1H, q, J=6.7 Hz), 5.01-5.10 (2H, m), 5.80-5.91 (1H,m), 6.16 (1H, s).

Step 5 (+)-1-(5-Chloro-1-methylpyrazol-3-yl)ethanol

The low polar isomer A (1.48 g) obtained in the preceding step 4 wasdissolved in methanol (45 ml). To the solution, p-toluenesulfonic acidmonohydrate (91 mg) was added at room temperature. After stirring atroom temperature for 3 hours, the solvent was distilled off underreduced pressure. Ethyl acetate and a saturated aqueous solution ofsodium bicarbonate were added to the residue to separate the aqueous andorganic layers. The organic layer was dried over anhydrous sodiumsulfate. Then, the solvent was distilled off under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane-ethyl acetate) to obtain the title compound (647 mg).

¹H-NMR (CDCl₃) δ: 1.49 (3H, d, J=6.7 Hz), 2.37 (1H, d, J=3.6 Hz), 3.79(3H, s), 4.84-4.89 (1H, m), 6.16 (1H, s).

[α]_(D)+16.7° (c=1.08, chloroform, 25.0° C.)

The following compounds were obtained by the same procedures as inReference Example 55.

TABLE 6 Reference Example Structure and name Instrumental data 56

¹H-NMR (CDCl₃) δ: 1.46 (3H, d, J = 6.6 Hz), 2.75 (1H, br s), 4.94-4.97(1H, m), 7.44-7.48 (1H, m), 8.30-8.32 (2H, m). [α]_(D) +43.44° (c =0.32, chloroform, 29.2° C.) (+)-1-(5-Fluoro-3-pyridyl)ethanol 57

¹H-NMR (CDCl₃) δ: 1.52 (3H, d, J = 6.7 Hz), 2.82- 2.85 (1H, br m), 4.94-4.97 (1H, m), 7.75-7.75 (1H, m), 8.42-8.43 (2H, m). [α]_(D) +44.44° (c =0.18, chloroform, 22.6° C.) (+)-1-(5-Chloro-3-pyridyl)ethanol

Reference Example 58 1-[5-Fluoro-2-(triazol-2-yl)phenyl]ethanol

Step 1 1-[5-Fluoro-2-(triazol-2-yl)phenyl]ethanone

1-(2,5-Difluorophenyl)ethanone (3.00 g) and 1H-triazole (1.99 g) weredissolved in N-methylpyrrolidone (5 ml). To the solution, potassiumcarbonate (2.66 g) was added, and the mixture was stirred at 140° C. for4.5 hours. After standing to cool, water and ethyl acetate were added tothe reaction solution to separate the aqueous and organic layers. Theaqueous layer was subjected to extraction with ethyl acetate. Theorganic layers were combined, washed three times with saturated saline,dried over anhydrous sodium sulfate and then concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate) to obtain the title compound(1.05 g).

¹H-NMR (CDCl₃) δ: 2.16 (3H, s), 7.22-7.31 (2H, m), 7.83-7.87 (3H, m).

1-[5-Fluoro-2-(triazol-2-yl)phenyl]ethanol

The compound (310 mg) obtained in the preceding step 1 was dissolved inmethanol (10 ml). To the solution, sodium borohydride (86 mg) was added,and the mixture was stirred at room temperature for 15 minutes. Thereaction solution was quenched by the addition of acetone. Water andethyl acetate were added to the reaction solution to separate theaqueous and organic layers. The organic layer was washed with saturatedsaline, dried over anhydrous sodium sulfate and then concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate) to obtain the title compound(296 mg).

¹H-NMR (CDCl₃) δ: 1.46 (3H, d, J=6.0 Hz), 3.94 (1H, d, J=4.2 Hz),4.83-4.89 (1H, m), 7.09-7.14 (1H, m), 7.39 (1H, dd, J=9.7, 3.0 Hz), 7.62(1H, dd, J=9.1, 5.4 Hz), 7.88 (2H, s).

Reference Example 59 1-[1-(Difluoromethyl)triazol-4-yl]ethanol

Step 1 1-[1-(Difluoromethyl)triazol-4-yl]ethanol

Tert-butanol (17.4 ml), water (17.4 ml), and a 1 M aqueous copper(II)sulfate solution (4.64 ml) were added to sodium chlorodifluoroacetate(3.54 g), but-3-yn-2-ol (2.00 ml), sodium azide (1.66 g), cesiumcarbonate (11.3 g), and copper (1.18 g), and the mixture was reacted for30 minutes using a microwave reaction apparatus (300 W, 125° C.). Thereaction solution was diluted with ethyl acetate. While being washed,the dilution was filtered to remove the aqueous layer. The organic layerwas dried over anhydrous sodium sulfate and then filtered. The solventwas distilled off under reduced pressure. The obtained residue waspurified by silica gel column chromatography (n-hexane-methyl acetate)to obtain the title compound (196 mg).

¹H-NMR (CDCl₃) δ: 1.64 (3H, d, J=6.0 Hz), 2.35-2.39 (1H, m), 5.11-5.19(1H, m), 7.54 (1H, t, J=59.2 Hz), 7.90 (1H, s).

Reference Example 60(+)-5-(1-Hydroxyethyl)-2-methylpyrazole-3-carbonitrile

Step 1 Ethyl 5-acetyl-2-methylpyrazole-3-carboxylate

Ethyl 3-acetyl-1H-pyrazole-5-carboxylate (Chem. Commun., 2004, 394-395)(4.82 g) was dissolved in N,N-dimethylformamide (80 ml). To thesolution, potassium carbonate (4.39 g) and iodomethane (1.98 ml) wereadded under ice cooling, and the mixture was stirred at room temperaturefor 3 hours and 50 minutes. The reaction solution was diluted with ethylacetate. The organic layer was washed with saturated saline, water, andsaturated saline in this order and then dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane-ethyl acetate) to obtain the title compound (3.38 g).

¹H-NMR (CDCl₃) δ: 1.38 (3H, t, J=7.1 Hz), 2.58 (3H, s), 4.24 (3H, s),4.36 (2H, q, J=7.1 Hz), 7.32 (1H, s).

Step 2 5-Acetyl-2-methylpyrazole-3-carbonitrile

The compound (3.38 g) obtained in the preceding step 1 was dissolved intetrahydrofuran (170 ml). To the solution, an aqueous solution (35 ml)of lithium hydroxide monohydrate (1.45 g) was added under ice cooling,and the mixture was stirred at room temperature for 2 hours and 45minutes. The reaction solution was rendered acidic by the addition of 1N hydrochloric acid under ice cooling, followed by extraction withdichloromethane. The extract was dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure. The obtainedresidue was dissolved in N,N-dimethylformamide (60 ml). To thissolution, 1-hydroxybenzotriazole (3.49 g) was added. Subsequently,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.95 g) andan aqueous ammonia solution (28%, 2.79 ml) were added to the mixtureunder ice cooling, and the resulting mixture was stirred overnight atroom temperature. Ethyl acetate and saturated saline were added to thereaction solution to separate two layers. Then, the aqueous layer wassubjected to extraction with ethyl acetate. The organic layers werecombined and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. The obtained residue was dissolvedin tetrahydrofuran (70 ml). To this solution, triethylamine (6.24 ml)and a solution of trifluoroacetic anhydride in tetrahydrofuran (22 ml)were added at −5° C. under a nitrogen atmosphere, and the mixture wasstirred for 3 hours and 40 minutes under ice cooling. Water was added tothe reaction solution, followed by extraction with ethyl acetate. Theextract was washed with saturated saline and then dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure.The obtained residue was purified by silica gel column chromatography(n-hexane-ethyl acetate) to obtain the title compound (2.36 g).

¹H-NMR (CDCl₃) δ: 2.59 (3H, s), 4.13 (3H, s), 7.26 (1H, s).

Step 3 5-(1-Hydroxyethyl)-2-methylpyrazole-3-carbonitrile

The compound (2.36 g) obtained in the preceding step 2 was dissolved inmethanol (170 ml). To this solution, sodium borohydride (658 mg) wasadded, and the mixture was stirred for 50 minutes. The reaction solutionwas concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (n-hexane-ethyl acetate) toobtain the title compound (1.75 g).

¹H-NMR (CDCl₃) δ:1.53 (3H, d, J=6.6 Hz), 2.15 (1H, d, J=4.3 Hz), 4.03(3H, s), 4.92-4.99 (1H, m), 6.74 (1H, s).

Step 45-[1-[[(3aR,6aR)-3a-Allyl-3,4,5,6-tetrahydro-2H-cyclopenta[b]furan-6a-yl]oxy]ethyl]-2-methylpyrazole-3-carbonitrile

The compound (1.75 g) obtained in the preceding step 3 was dissolved indichloromethane (60 ml). To the solution, p-toluenesulfonic acidpyridine salt (232 mg) was added under ice cooling. A solution of(3aR)-3a-allyl-2,3,4,5-tetrahydrocyclopenta[b]furan (2.09 g) indichloromethane (35 ml) was further added to the mixture, and theresulting mixture was stirred at room temperature for 2 hours and 20minutes. A saturated aqueous solution of sodium bicarbonate was added tothe reaction solution, followed by extraction with dichloromethane. Theextract was dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (n-hexane-ethyl acetate) to obtainlow polar isomer A (1.56 g) and highly polar isomer B (1.62 g).

Low polar isomer A (Rf=0.70, n-hexane:ethyl acetate=7:3)

¹H-NMR (CDCl₃) δ: 1.26-1.37 (1H, m), 1.44 (3H, d, J=6.7 Hz), 1.47-1.62(4H, m), 1.68-1.76 (1H, m), 1.93-2.11 (3H, m), 2.28-2.35 (1H, m),3.80-3.91 (2H, m), 4.00 (3H, s), 4.97-5.10 (3H, m), 5.79-5.90 (1H, m),7.26 (1H, s).

Highly polar isomer B (Rf=0.63, n-hexane:ethyl acetate=7:3)

¹H-NMR (CDCl₃) δ: 1.43 (3H, d, J=6.7 Hz), 1.47-1.73 (6H, m), 1.88-1.94(1H, m), 2.10-2.31 (3H, m), 3.46-3.55 (1H, m), 3.67-3.74 (1H, m), 4.00(3H, s), 4.96 (1H, q, J=6.7 Hz), 5.02-5.11 (2H, m), 5.80-5.90 (1H, m),6.73 (1H, s).

Step 5 (+)-5-(1-Hydroxyethyl)-2-methylpyrazole-3-carbonitrile

The low polar isomer A (1.56 g) obtained in the preceding step 4 wasdissolved in methanol (52 ml). To the solution, p-toluenesulfonic acidmonohydrate (1.48 g) was added at room temperature. After stirring at50° C. for 2 hours, the solvent was distilled off under reducedpressure. Dichloromethane and a saturated aqueous solution of sodiumbicarbonate were added to the residue to separate the aqueous andorganic layers. The organic layer was dried over anhydrous sodiumsulfate. Then, the solvent was distilled off under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane-ethyl acetate) to obtain the title compound (709 mg).

¹H-NMR (CDCl₃) δ: 1.53 (3H, d, J=6.6 Hz), 2.15 (1H, d, J=4.3 Hz), 4.03(3H, s), 4.92-4.99 (1H, m), 6.74 (1H, s). [α]_(D)+19.0° (c=1.05,chloroform, 25.0° C.)

Reference Example 61 tert-ButylN-[5-oxo-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-3-yl]carbamate

Step 1 1-(4-Bromophenyl)-5-oxopyrrolidine-3-carboxylic acid

A mixture of 4-bromoaniline (8.6 g) and itaconic acid (6.5 g) wasstirred at 130° C. for 50 minutes. After cooling, a n-hexane-ethylacetate mixed solution was added to the resulting solid. The compoundwas collected by filtration to obtain the title compound (13.5 g).

¹H-NMR (CDCl₃) δ: 2.89-3.03 (2H, m), 3.38-3.47 (1H, m), 4.02-4.16 (2H,m), 7.49 (4H, s).

Step 2 tert-Butyl N-[1-(4-bromophenyl)-5-oxopyrrolidin-3-yl]carbamate

To a solution of the compound (2.8 g) obtained in the preceding step 1in tert-butanol (40 ml), triethylamine (2.1 ml) and diphenylphosphorylazide (2.6 ml) were added, and the mixture was stirred at roomtemperature for 1 hour and then stirred at 80° C. for 3 hours. Aftercooling, the reaction solution was concentrated under reduced pressure,and a saturated aqueous solution of sodium bicarbonate was added to theresidue, followed by extraction with ethyl acetate. The extract waswashed with saturated saline and then dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure. Theobtained residue was purified by silica gel column chromatography(chloroform) to obtain the title compound (2.0 g).

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 2.48 (1H, dd, J=17.2, 4.6 Hz), 2.97 (1H,dd, J=17.2, 8.0 Hz), 3.70 (1H, d, J=10.9 Hz), 4.14 (1H, t, J=8.0 Hz),4.41 (1H, br s), 4.85 (1H, br s), 7.46-7.52 (4H, m).

Step 3 tert-ButylN-[5-oxo-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-3-yl]carbamate

To a solution of the compound (0.9 g) obtained in the preceding step 2in 1,4-dioxane (20 ml), bis(pinacolato)diborane (0.77 g), potassiumacetate (0.75 g), and a[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethaneadduct (0.21 g) were added, and the mixture was stirred at 80° C. for 6hours under a nitrogen atmosphere. After cooling, ethyl acetate wasadded to the reaction solution, and the insoluble matter was filteredoff. The filtrate was concentrated under reduced pressure. Then, theobtained residue was purified by silica gel column chromatography(n-hexane-ethyl acetate) to obtain the title compound (1.0 g).

¹H-NMR (CDCl₃) δ: 1.34 (12H, s), 1.45 (9H, s), 2.49 (1H, dd, J=17.8, 4.6Hz), 2.98 (1H, dd, J=17.2, 8.0 Hz), 3.74 (1H, d, J=6.9 Hz), 4.15-4.21(1H, m), 4.37-4.47 (1H, m), 4.85 (1H, br s), 7.61 (2H, d, J=8.6 Hz),7.81 (2H, d, J=8.6 Hz).

Reference Example 62 tert-ButylN-[(3R)-5-oxo-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-3-yl]carbamate

Step 1 tert-ButylN-[(3R)-1-(4-bromophenyl)-5-oxopyrrolidin-3-yl]carbamate

1,4-Dioxane (8 ml) was added to 1,4-dibromobenzene (176 mg), t-butylN-[(3R)-5-oxopyrrolidin-3-yl]carbamate (100 mg),tris(dibenzylideneacetone)dipalladium(0) (23 mg),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (29 mg), and cesiumcarbonate (244 mg), and the mixture was stirred at 90° C. for 1 hourunder an argon atmosphere and then further heated to reflux for 1 hour.Dichloromethane and water were added to the reaction solution toseparate the aqueous and organic layers. The organic layer was driedover anhydrous sodium sulfate and then concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate) to obtain the title compound (24mg).

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 2.49 (1H, dd, J=17.2, 4.6 Hz), 2.96 (1H,dd, J=17.2, 8.0 Hz), 3.69 (1H, dd, J=10.0, 3.2 Hz), 4.12 (1H, dd,J=10.0, 7.2 Hz), 4.41 (1H, br s), 4.96 (1H, d, J=7.2 Hz), 7.46-7.50 (4H,m).

ESI-MS (m/z): 355, 357 (M+H)⁺.

Reference Example 63 tert-ButylN-[[5-oxo-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-3-yl]methyl]carbamate

Step 1 1-(4-Bromophenyl)-4-(hydroxymethyl)pyrrolidin-2-one

To a solution of the compound (2.8 g) obtained in step 1 of ReferenceExample 61 in tetrahydrofuran (30 ml), a borane-tetrahydrofuran complex(0.98 M solution in tetrahydrofuran, 20.4 ml) was added under icecooling, and the mixture was stirred at the same temperature as abovefor 1 hour. A saturated aqueous solution of sodium bicarbonate was addedto the reaction solution, followed by extraction with ethyl acetate. Theextract was washed with saturated saline and then dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure.The obtained residue was purified by silica gel column chromatography(n-hexane-ethyl acetate) to obtain the title compound (1.3 g).

¹H-NMR (CDCl₃) δ: 1.67 (1H, br s), 2.39-2.49 (1H, m), 2.65-2.77 (2H, m),3.67-3.81 (3H, m), 3.93 (1H, dd, J=9.6, 7.8 Hz), 7.47 (2H, d, J=9.2 Hz),7.54 (2H, d, J=8.7 Hz).

Step 2 [1-(4-Bromophenyl)-5-oxo-pyrrolidin-3-yl]methyl methanesulfonate

To a solution of the compound (1.3 g) obtained in the preceding step 1in dichloromethane (30 ml), triethylamine (1.3 ml) and methanesulfonylchloride (0.56 ml) were added under ice cooling, and the mixture wasstirred at room temperature for 4 hours. Water was added to the reactionsolution to separate two layers. Then, the aqueous layer was subjectedto extraction with chloroform. The organic layers were combined, washedwith saturated saline and then dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure to obtain the titlecompound (1.6 g).

¹H-NMR (CDCl₃) δ: 2.46 (1H, dd, J=17.8, 6.9 Hz), 2.82 (1H, dd, J=17.2,9.2 Hz), 2.91-3.00 (1H, m), 3.06 (3H, s), 3.73 (1H, dd, J=10.3, 5.7 Hz),4.00 (1H, dd, J=9.7, 8.0 Hz), 4.26 (1H, dd, J=10.0, 7.7 Hz), 4.34 (1H,dd, J=10.3, 5.7 Hz), 7.46-7.53 (4H, m).

Step 32-[[1-(4-Bromophenyl)-5-oxo-pyrrolidin-3-yl]methyl]isoindoline-1,3-dione

To a solution of the compound (0.5 g) obtained in the preceding step 2in N,N-dimethylformamide (20 ml), sodium iodide (0.26 g) and phthalimidepotassium (0.32 g) were added, and the mixture was stirred at 70° C. for4 hours. After cooling, water was added to the reaction solution,followed by extraction with ethyl acetate. The extract was washed withwater and saturated saline in this order and then dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure.The obtained residue was washed with an ethyl acetate-diethyl ethermixed solvent to obtain the title compound (0.38 g).

¹H-NMR (CDCl₃) δ: 2.50 (1H, dd, J=17.0, 7.3 Hz), 2.77 (1H, dd, J=17.0,8.7 Hz), 2.88-3.01 (1H, m), 3.73 (1H, dd, J=10.1, 6.0 Hz), 3.82-3.91(3H, m), 7.43-7.51 (4H, m), 7.74-7.79 (2H, m), 7.85-7.91 (2H, m).

Step 4 tert-ButylN-[[1-(4-bromophenyl)-5-oxopyrrolidin-3-yl]methyl]carbamate

To a solution of the compound (0.38 g) obtained in the preceding step 3in ethanol (20 ml), hydrazine hydrate (0.11 ml) was added, and themixture was stirred at room temperature for 24 hours. The reactionsolution was concentrated under reduced pressure. Then, chloroform wasadded to the residue, and the insoluble matter was filtered off. Thefiltrate was concentrated under reduced pressure. Ethanol (10 ml) anddi-tert-butyl dicarbonate (0.33 g) were added to the obtained residue,and the mixture was stirred at room temperature for 1 hour. The reactionsolution was concentrated under reduced pressure. Then, the obtainedresidue was purified by silica gel column chromatography (n-hexane-ethylacetate) to obtain the title compound (0.31 g).

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 2.34-2.40 (1H, m), 2.65-2.76 (2H, m),3.27 (2H, br s), 3.60 (1H, dd, J=10.3, 5.7 Hz), 3.90 (1H, dd, J=9.7, 6.9Hz), 4.75 (1H, s), 7.47 (2H, d, J=8.6 Hz), 7.51 (2H, d, J=9.2 Hz).

Step 5 tert-ButylN-[[5-oxo-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-3-yl]methyl]carbamate

The title compound (0.33 g) was obtained by the same procedures as instep 3 of Reference Example 61 using the compound (0.31 g) obtained inthe preceding step 4.

¹H-NMR (CDCl₃) δ: 1.24 (12H, s), 1.44 (9H, s), 2.39 (1H, dd, J=16.0, 5.7Hz), 2.67-2.78 (2H, m), 3.27 (2H, br s), 3.63 (1H, dd, J=9.7, 5.7 Hz),3.94 (1H, dd, J=9.7, 8.0 Hz), 4.75 (1H, s), 7.62 (2H, d, J=8.6 Hz), 7.80(2H, d, J=8.0 Hz).

Reference Example 64 tert-ButylN-[2-oxo-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-3-yl]carbamate

Step 1 2,4-Dibromo-N-(4-bromophenyl)butanamide

To a solution of 4-bromoaniline (1.73 g) in dichloromethane (40 ml),triethylamine (2.8 ml) and a solution of 2,4-dibromobutyryl chloride(3.2 g) in dichloromethane (10 ml) were added under ice cooling, and themixture was stirred at room temperature for 5 hours. After addition of 1N hydrochloric acid to the reaction solution, the mixture was separatedinto two layers. The aqueous layer was subjected to extraction withchloroform. The organic layers were combined, washed with a saturatedaqueous solution of sodium bicarbonate and saturated saline in thisorder and then dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure to obtain a crude product of thetitle compound, which was used in the next reaction without beingpurified.

Step 2 3-Bromo-1-(4-bromophenyl)pyrrolidin-2-one

To a solution of the compound obtained in the preceding step 1 inN,N-dimethylformamide (30 ml), sodium hydride (55% oil, 0.65 g) wasadded under ice cooling, and the mixture was stirred at the sametemperature as above for 1 hour. A saturated aqueous solution of sodiumchloride was added to the reaction solution, followed by extraction withethyl acetate. The extract was washed with water and saturated saline inthis order and then dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (n-hexane-ethyl acetate) and thenwashed with n-hexane to obtain the title compound (1.2 g).

¹H-NMR (CDCl₃) δ: 2.43-2.50 (1H, m), 2.69-2.77 (1H, m), 3.78-3.83 (1H,m), 4.00-4.06 (1H, m), 4.58 (1H, dd, J=6.9, 2.9 Hz), 7.51 (2H, d, J=9.2Hz), 7.56 (2H, d, J=9.2 Hz).

Step 3 2-[1-(4-Bromophenyl)-2-oxo-pyrrolidin-3-yl]isoindoline-1,3-dione

To a solution of the compound (0.7 g) obtained in the preceding step 2in N,N-dimethylformamide (20 ml), phthalimide potassium (0.51 g) wasadded, and the mixture was stirred at 70° C. for 1 hour. After cooling,water was added to the reaction solution, followed by extraction withethyl acetate. The extract was washed with water and saturated saline inthis order and then dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. The obtained residue was washedwith diethyl ether to obtain the title compound (0.35 g).

¹H-NMR (CDCl₃) δ: 2.53-2.67 (2H, m), 3.87-4.02 (2H, m), 5.14 (1H, t,J=9.9 Hz), 7.51 (2H, d, J=9.5 Hz), 7.59 (2H, d, J=9.5 Hz), 7.73-7.78(2H, m), 7.85-7.90 (2H, m).

Step 4 tert-Butyl N-[1-(4-bromophenyl)-2-oxopyrrolidin-3-yl]carbamate

The title compound (0.39 g) was obtained by the same procedures as instep 4 of Reference Example 63 using the compound (0.35 g) obtained inthe preceding step 3.

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 1.96-2.07 (2H, m), 2.79 (1H, br s),3.74-3.80 (1H, m), 4.34 (1H, br s), 5.20 (1H, s), 7.49 (2H, d, J=9.2Hz), 7.55 (2H, d, J=9.7 Hz).

Step 5 tert-ButylN-[2-oxo-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-3-yl]carbamate

The title compound (0.52 g) was obtained by the same procedures as instep 3 of Reference Example 61 using the compound (0.39 g) obtained inthe preceding step 4.

¹H-NMR (CDCl₃) δ: 1.24 (12H, s), 1.47 (9H, s), 1.96-2.04 (1H, m), 2.80(1H, br s), 3.80 (1H, d, J=5.0 Hz), 3.83 (1H, d, J=4.1 Hz), 4.36 (1H, brs), 5.22 (1H, br s), 7.66 (2H, d, J=8.3 Hz), 7.82 (2H, d, J=9.2 Hz).

Reference Example 65 tert-ButylN-[(3S)-5-oxo-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-3-yl]carbamate

Step 1 tert-ButylN-[(1S)-3-(4-bromoanilino)-1-(hydroxymethyl)-3-oxopropyl]carbamate

4-Bromoaniline (172 mg) was dissolved in dichloromethane (5 ml). To thesolution, trimethylaluminum (1.8 M solution in toluene, 0.556 ml) wasadded, and the mixture was stirred at room temperature for 15 minutes.Tert-butyl N-[(3S)-5-oxotetrahydrofuran-3-yl]carbamate (201 mg) wasadded to the reaction solution, and the mixture was stirred overnight atroom temperature, then stirred at 60° C. for 1 hour, and then furtherheated to reflux for 1 hour.

The same procedures as above were performed using 4-bromoaniline (2.56g), and two lots were combined. Water was added to the reactionsolution, followed by extraction from the aqueous layer with ethylacetate. The aqueous layer was filtered through celite. After extractionfrom the filtrate with dichloromethane, these two organic layers werecombined, dried over anhydrous sodium sulfate and then concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (n-hexane-ethyl acetate) to obtain the titlecompound (3.82 g).

¹H-NMR (DMSO-d₆) δ: 1.34 (9H, s), 2.39 (1H, dd, J=14.9, 7.4 Hz), 2.54(1H, dd, J=14.9, 5.7 Hz), 3.28-3.35 (1H, m), 3.36-3.41 (1H, m),3.82-3.88 (1H, m), 4.70-4.78 (1H, m), 6.59 (1H, d, J=8.6 Hz), 7.45-7.48(2H, m), 7.54-7.57 (2H, m), 9.97 (1H, s).

ESI-MS (m/z): 373, 375 (M+H)⁺.

Step 2 tert-ButylN-[(3S)-1-(4-bromophenyl)-5-oxopyrrolidin-3-yl]carbamate

The compound (100 mg) obtained in the preceding step 1 was dissolved intetrahydrofuran (5 ml). To the solution, di-tert-butyl azodicarboxylate(74 mg) and tributylphosphine (80 μl) were added, and the mixture wasstirred at 60° C. for 1 hour and then heated to reflux for 2 hours.Di-tert-butyl azodicarboxylate (148 mg) and tributylphosphine (160 μl)were further added thereto, and the mixture was further heated to refluxfor 1.5 hours.

The same procedures as above were performed using the compound (3.09 g)obtained in the preceding step 1, and two lots were combined. Thereaction solution was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (n-hexane-ethylacetate) to obtain the title compound (1.78 g).

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 2.49 (1H, dd, J=17.5, 4.6 Hz), 2.97 (1H,dd, J=17.5, 8.0 Hz), 3.70 (1H, dd, J=10.3, 3.4 Hz), 4.14 (1H, dd,J=10.3, 6.9 Hz), 4.42 (1H, br s), 4.87 (1H, br s), 7.46-7.51 (4H, m).

ESI-MS (m/z): 355, 357 (M+H)⁺.

Step 3 tert-ButylN-[(3S)-5-oxo-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-3-yl]carbamate

The title compound (0.148 g) was obtained by the same procedures as instep 3 of Reference Example 61 using the compound (0.200 g) obtained inthe preceding step 2.

¹H-NMR (CDCl₃) δ: 1.34 (12H, s), 1.45 (9H, s), 2.49 (1H, dd, J=17.2, 4.6Hz), 2.98 (1H, dd, J=17.2, 8.0 Hz), 3.73 (1H, dd, J=10.3, 3.4 Hz), 4.18(1H, dd, J=10.3, 6.3 Hz), 4.42 (1H, br s), 4.85 (1H, br s), 7.59-7.62(2H, m), 7.80-7.82 (2H, m).

ESI-MS (m/z): 403 (M+H)⁺.

The following compounds were obtained by the same procedures as inReference Example 65.

TABLE 7 Reference Example Structure and name Instrumental data 66

¹H-NMR (CDCl₃) δ: 1.34 (12H, s), 1.46 (9H, s), 2.48 (1H, dd, J = 17.2,4.1 Hz), 2.97 (1H, dd, J = 17.2, 7.8 Hz), 3.77 (1H, d, J = 9.8 Hz),4.20-4.23 (1H, m), 4.43 (1H, br s), 4.86 (1H, br s), 7.39 (1H, t, J =7.6 Hz), 7.61 (1H, d, J = 6.8 Hz), 7.69 (1H, s), 7.93-7.96 (1H, m).tert-Butyl N-[(3S)-5-oxo-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]pyrrolidin-3-yl]carbamate 67

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.46 (9H, s), 2.45 (1H, dd, J = 17.3,4.6 Hz), 2.92 (1H, dd, J = 17.3, 8.1 Hz), 3.70 (1H, dd, J = 10.7, 3.4Hz), 4.12-4.16 (1H, m), 4.46 (1H, br s), 4.89 (1H, br s), 7.45 (1H, t, J= 7.6 Hz), 7.56 (1H, d, J = 11.2 Hz), 7.59 (1H, dd, J = 7.6, 1.0 Hz).tert-Butyl N-[(3S)-1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-oxopyrrolidin-3-yl]carbamate 68

¹H-NMR (CDCl₃) δ: 1.36 (12H, s), 1.46 (9H, s), 2.51 (1H, dd, J = 17.3,4.6 Hz), 2.98 (1H, dd, J = 17.3, 8.1 Hz), 3.70-3.73 (1H, m), 4.10- 4.16(1H, m), 4.42 (1H, br s), 4.92 (1H, br s), 7.32 (1H, dd, J = 8.3, 2.0Hz), 7.51 (1H, t, J = 8.3 Hz), 7.72 (1H, t, J = 7.6 Hz). tert-ButylN-[(3S)-1-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-oxopyrrolidin-3-yl]carbamate 69

¹H-NMR (CDCl₃) δ: 1.34 (12H, s), 1.45 (9H, s), 2.46- 2.53 (1H, m),2.94-3.02 (1H, m), 3.69-3.75 (1H, m), 3.85 (3H, s), 4.09-4.19 (1H, m),4.37-4.46 (1H, br m), 4.84- 4.90 (1H, br m), 6.85-6.90 (1H, m), 7.56(1H, d, J = 1.8 Hz), 7.66 (1H, d, J = 8.5 Hz). tert-ButylN-[(3S)-1-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-oxopyrrolidin-3-yl]carbamate

Reference Example 70 tert-ButylN-[(3S)-5-oxo-1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]pyrrolidin-3-yl]carbamate

Step 1 tert-ButylN-[(1S)-3-[(5-bromo-2-pyridyl)amino]-1-(hydroxymethyl)-3-oxopropyl]carbamate

The title compound (0.53 g) was obtained by the same procedures as instep 1 of Reference Example 65 using 2-amino-5-bromopyridine (0.66 g)instead of 4-bromoaniline.

¹H-NMR (CDCl₃) δ: 1.42 (9H, s), 2.76-2.80 (2H, m), 3.56 (1H, br s),3.72-3.78 (1H, m), 3.80-3.87 (1H, m), 4.02-4.10 (1H, m), 5.64-5.67 (1H,m), 7.79 (1H, dd, J=9.0, 2.6 Hz), 8.12 (1H, d, J=9.0 Hz), 8.33 (1H, d,J=2.6 Hz), 8.87 (1H, s).

ESI-MS (m/z): 374, 376 (M+H)⁺.

Step 2 tert-ButylN-[(3S)-1-(5-bromo-2-pyridyl)-5-oxopyrrolidin-3-yl]carbamate

The title compound (0.59 g) was obtained by the same procedures as instep 2 of Reference Example 65 using the compound (0.53 g) obtained inthe preceding step 1.

¹H-NMR (CDCl₃) δ: 1.43 (9H, s), 2.55 (1H, dd, J=17.6, 4.3 Hz), 2.99 (1H,dd, J=17.6, 7.8 Hz), 3.91-3.97 (1H, m), 4.28 (1H, dd, J=11.9, 6.8 Hz),4.37 (1H, br s), 4.81 (1H, br s), 7.76 (1H, dd, J=9.0, 2.3 Hz), 8.29(1H, d, J=9.0 Hz), 8.35 (1H, d, J=2.3 Hz).

ESI-MS (m/z): 356, 358 (M+H)⁺.

Reference Example 71 tert-ButylN-methyl-N-[(3S)-5-oxo-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-3-yl]carbamate

Step 1 tert-ButylN-methyl-N-[(3S)-5-oxo-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-3-yl]carbamate

To a solution of the compound (500 mg) obtained in step 3 of ReferenceExample 65 in N,N-dimethylformamide (10 ml), cesium carbonate (405 mg)and iodomethane (77 μl) were added, and the mixture was stirred at roomtemperature for 1 hour. Sodium hydride (55% oil, 60 mg) was addedthereto, and the mixture was stirred at room temperature for 2 hours.Sodium hydride (60 mg) and iodomethane (77 μl) were further addedthereto, and the mixture was further stirred at room temperature for 1hour. Ethyl acetate and water were added to the reaction solution toseparate the aqueous and organic layers. The aqueous layer was subjectedto extraction with ethyl acetate. The organic layers were combined,dried over anhydrous sodium sulfate and then concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate) to obtain the title compound(192 mg).

¹H-NMR (CDCl₃) δ: 1.34 (12H, s), 1.47 (9H, s), 2.68 (1H, dd, J=17.5, 5.4Hz), 2.85 (3H, s), 2.89-2.96 (1H, m), 3.73-3.79 (1H, m), 4.10-4.15 (1H,m), 4.41-4.83 (1H, m), 7.64 (2H, d, J=8.5 Hz), 7.82 (2H, d, J=8.5 Hz).

ESI-MS (m/z): 417 (M+H)⁺.

Reference Example 72 tert-ButylN-[(3S)-1-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-oxopyrrolidin-3-yl]carbamate

Step 1 tert-ButylN-[(3S)-1-(4-bromo-3-methylphenyl)-5-oxopyrrolidin-3-yl]carbamate

A suspension of 2-bromo-5-iodotoluene (1.5 g), tert-butyl((S)-5-oxopyrrolidin-3-yl)carbamate (2.7 g), copper iodide (95 mg),cesium fluoride (1.9 g), and N,N-dimethylethylenediamine (0.11 ml) inacetonitrile (20 ml) was stirred at 100° C. for 3 hours under a nitrogenatmosphere. After cooling, a saturated aqueous solution of ammoniumchloride was added to the reaction solution, followed by extraction withethyl acetate. The extract was washed with a 10% aqueous sodiumthiosulfate solution and saturated saline in this order and then driedover anhydrous sodium sulfate. The solvent was distilled off underreduced pressure. The obtained residue was purified by silica gel columnchromatography (chloroform-methanol) to obtain the title compound (1.8g).

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 2.40 (3H, s), 2.47 (1H, dd, J=17.2, 4.5Hz), 2.96 (1H, dd, J=17.2, 8.2 Hz), 3.69 (1H, d, J=9.7 Hz), 4.13 (1H,dd, J=9.7, 6.7 Hz), 4.41 (1H, br s), 4.83 (1H, br s), 7.29 (1H, d, J=8.5Hz), 7.47-7.52 (2H, m).

Step 2 tert-ButylN-[(3S)-1-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-oxopyrrolidin-3-yl]carbamate

The title compound (1.5 g) was obtained by the same procedures as instep 3 of Reference Example 61 using the compound (1.0 g) obtained inthe preceding step 1.

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.45 (9H, s), 2.48 (1H, dd, J=17.2, 4.5Hz), 2.54 (3H, s), 2.97 (1H, dd, J=17.2, 8.2 Hz), 3.71 (1H, d, J=7.3Hz), 4.10-4.18 (1H, m), 4.42 (1H, br s), 4.85 (1H, br s), 7.34-7.44 (2H,m), 7.76 (1H, d, J=8.5 Hz).

The following compounds were obtained by the same procedures as inReference Example 72.

TABLE 8 Reference Example Structure and name Instrumental data 73

¹H-NMR (CDCl₃) δ: 1.04- 1.30 (4H, m), 1.26 (3H, s), 1.27 (12H, s), 1.40(9H, s), 3.75 (1H, d, J = 10.3 Hz), 4.62 (2H, br s), 7.66 (2H, d, J =8.5 Hz), 7.81 (2H, d, J = 8.5 Hz). tert-ButylN-[7-methyl-4-oxo-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-azaspiro[2.4]heptan-7-yl]carbamate 74

¹H-NMR (CDCl₃) δ: 1.33 (12H, s), 1.46 (9H, s), 2.24 (3H, s), 2.44 (1H,dd, J = 17.5, 4.8 Hz), 2.94 (1H, dd, J = 17.5, 7.9 Hz), 3.59 (1H, dd, J= 10.3, 4.2 Hz), 3.97- 4.05 (1H, m), 4.45 (1H, br s), 4.91 (1H, d, J =6.0 Hz), 7.13 (1H, d, J = 7.9 Hz), 7.67 (1H, d, J = 7.9 Hz), 7.73 (1H,s). tert-Butyl N-[(3S)-1-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-oxopyrrolidin-3-yl]carbamate

Reference Example 75 tert-ButylN-[3-methyl-5-oxo-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-3-yl]carbamate

Step 1 Methyl 1-[(4-methoxyphenyl)methyl]-5-oxopyrrolidine-3-carboxylate

A mixture of (4-methoxyphenyl)methanamine (6.9 g) and dimethyl itaconate(7.9 g) was stirred at 120° C. for 2 hours. After cooling, ethyl acetatewas added to the reaction solution. The organic layer was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate,and saturated saline in this order and then dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure to obtainthe title compound (12.7 g).

¹H-NMR (CDCl₃) δ: 2.62-2.77 (2H, m), 3.10-3.20 (1H, m), 3.41 (1H, d,J=7.8 Hz), 3.67 (3H, s), 3.75 (1H, d, J=8.6 Hz), 3.76 (3H, s), 4.32 (1H,d, J=15.2 Hz), 4.40 (1H, d, J=15.6 Hz), 6.83 (2H, d, J=8.2 Hz), 7.13(2H, d, J=8.7 Hz).

Step 2 Methyl1-[(4-methoxyphenyl)methyl]-3-methyl-5-oxopyrrolidine-3-carboxylate

To a solution of the compound (9.8 g) obtained in the preceding step 1in N,N-dimethylformamide (100 ml), methyl iodide (23.2 ml) and sodiumhydride (55% oil, 6.5 g) were added, and the mixture was stirred at roomtemperature for 7.5 hours. Water was added to the reaction solution,followed by extraction with ethyl acetate. The extract was washed withwater and saturated saline in this order and then dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure toobtain a crude product of the title compound, which was used directly inthe next reaction.

Step 31-[(4-Methoxyphenyl)methyl]-3-methyl-5-oxopyrrolidine-3-carboxylic acid

To a methanol (50 ml)-tetrahydrofuran (50 ml) mixed solution of thecompound obtained in the preceding step 2, a 1 N aqueous sodiumhydroxide solution (50 ml) was added, and the mixture was stirred atroom temperature for 3.5 hours. The reaction solution was concentratedunder reduced pressure. Then, the residue was made acidic by theaddition of concentrated hydrochloric acid, followed by extraction withethyl acetate. The extract was washed with saturated saline and thendried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure. The obtained residue was washed with an-hexane-diethyl ether mixed solution to obtain the title compound (7.3g).

¹H-NMR (CDCl₃) δ: 1.38 (3H, s), 2.38 (1H, d, J=17.1 Hz), 3.02 (1H, d,J=17.1 Hz), 3.02 (1H, d, J=9.8 Hz), 3.66 (1H, d, J=10.4 Hz), 3.80 (3H,s), 4.31 (1H, d, J=14.6 Hz), 4.49 (1H, d, J=14.6 Hz), 6.86 (2H, d, J 9.2Hz), 7.16 (2H, d, J=8.5 Hz).

Step 4 4-Amino-1-[(4-methoxyphenyl)methyl]-4-methylpyrrolidin-2-one

To a solution of the compound (4.5 g) obtained in the preceding step 3in toluene (50 ml), triethylamine (4.8 ml) and diphenylphosphoryl azide(4.4 ml) were added, and the mixture was heated to reflux for 3 hours.After cooling, the reaction solution was concentrated under reducedpressure. 1,4-Dioxane (40 ml), water (20 ml), and concentratedhydrochloric acid (20 ml) were added to the obtained residue, and themixture was stirred at 50° C. for 5 hours. After cooling, water wasadded to the reaction solution, and the aqueous layer was washed withethyl acetate. The aqueous layer was made alkaline by the addition of a10 N aqueous sodium hydroxide solution, followed by extraction withchloroform. The extract was washed with saturated saline and then driedover anhydrous sodium sulfate. The solvent was distilled off underreduced pressure to obtain a crude product of the title compound (4.0g), which was used directly in the next reaction.

¹H-NMR (CDCl₃) δ: 1.28 (3H, s), 1.57 (2H, br s), 2.39 (1H, d, J=16.9Hz), 2.46 (1H, d, J=16.9 Hz), 3.04 (1H, d, J=9.7 Hz), 3.12 (1H, d, J=9.7Hz), 3.80 (3H, s), 4.35 (1H, d, J=14.5 Hz), 4.43 (1H, d, J=15.1 Hz),6.86 (2H, d, J=8.5 Hz), 7.17 (2H, d, J=9.1 Hz).

Step 5 tert-ButylN-[1-[(4-methoxyphenyl)methyl]-3-methyl-5-oxopyrrolidin-3-yl]carbamate

To a solution of the compound (4.0 g) obtained in the preceding step 4in ethanol (50 ml), di-tert-butyl dicarbonate (5.6 g) was added, and themixture was stirred at room temperature for 2 hours. The reactionsolution was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (n-hexane-ethylacetate) to obtain the title compound (2.8 g).

¹H-NMR (CDCl₃) δ: 1.39 (3H, s), 1.40 (9H, s), 2.40 (1H, d, J=16.9 Hz),2.78 (1H, d, J=16.9 Hz), 3.15 (1H, d, J=10.3 Hz), 3.57 (1H, d, J=10.9Hz), 3.79 (3H, s), 4.31 (1H, d, J=14.5 Hz), 4.48 (1H, d, J=14.5 Hz),4.61 (1H, br s), 6.85 (2H, d, J=8.5 Hz), 7.16 (2H, d, J=8.5 Hz).

Step 6 tert-Butyl N-(3-methyl-5-oxopyrrolidin-3-yl)carbamate

To a solution of the compound (0.55 g) obtained in the preceding step 5in toluene (20 ml), methanesulfonic acid (0.43 ml) was added, and themixture was heated to reflux for 5 hours. After cooling, the reactionsolution was concentrated under reduced pressure. The obtained residuewas dissolved in 1,4-dioxane (10 ml). To this solution, a saturatedaqueous solution of sodium bicarbonate was added to make the solutionalkaline. Then, di-tert-butyl dicarbonate (0.53 g) was added to themixture, and the resulting mixture was stirred at room temperature for22 hours. The reaction solution was concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(chloroform-methanol) to obtain the title compound (0.2 g).

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 1.50 (3H, s), 2.28 (1H, d, J=16.3 Hz),2.75 (1H, d, J=16.3 Hz), 3.30 (1H, d, J=9.7 Hz), 3.74 (1H, d, J=9.7 Hz),4.70 (1H, br s), 5.47 (1H, br s).

Step 7 tert-ButylN-[1-(4-bromophenyl)-3-methyl-5-oxopyrrolidin-3-yl]carbamate

The title compound (0.65 g) was obtained by the same procedures as instep 1 of Reference Example 72 using the compound (0.9 g) obtained inthe preceding step 6.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 1.56 (3H, s), 2.56 (1H, d, J=16.9 Hz),3.00 (1H, d, J=16.3 Hz), 3.72 (1H, d, J=10.3 Hz), 4.22 (1H, d, J=9.1Hz), 4.75 (1H, br s), 7.47 (2H, d, J=9.1 Hz), 7.51 (2H, d, J=9.1 Hz).

Step 8 tert-ButylN-[3-methyl-5-oxo-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-3-yl]carbamate

A crude product of the title compound (1.0 g) was obtained by the sameprocedures as in step 3 of Reference Example 61 using the compound (0.65g) obtained in the preceding step 7.

¹H-NMR (CDCl₃) δ: 1.34 (12H, s), 1.44 (9H, s), 1.56 (3H, s), 2.58 (1H,d, J=16.9 Hz), 3.00 (1H, d, J=16.9 Hz), 3.78 (1H, d, J=10.3 Hz), 4.23(1H, d, J=10.3 Hz), 4.76 (1H, br s), 7.62 (2H, d, J=9.1 Hz), 7.80 (2H,d, J=8.5 Hz).

Reference Example 76 tert-ButylN-[(3S)-1-(4-bromo-2-cyanophenyl)-5-oxopyrrolidin-3-yl]carbamate

Step 1 tert-ButylN-[(3S)-1-(4-bromo-2-cyanophenyl)-5-oxopyrrolidin-3-yl]carbamate

To a solution of tert-butyl ((S)-5-oxopyrrolidin-3-yl)carbamate (2.0 g)in N,N-dimethylformamide (50 ml), sodium hydride (55% oil, 0.65 g) wasadded under ice cooling, and the mixture was stirred at the sametemperature as above for 10 minutes. 5-Bromo-2-fluorobenzonitrile (3.0g) was added to the reaction solution, and the mixture was stirred atroom temperature for 1 hour. Ice water and a saturated aqueous solutionof ammonium chloride were added to the reaction solution, followed byextraction with ethyl acetate. The extract was washed with water andsaturated saline in this order and then dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure. Theobtained residue was purified by silica gel column chromatography(n-hexane-ethyl acetate) to obtain the title compound (1.5 g).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.52 (1H, dd, J=17.5, 4.8 Hz), 2.96 (1H,dd, J=17.5, 7.9 Hz), 3.81 (1H, d, J=6.7 Hz), 4.19 (1H, dd, J=10.0, 6.3Hz), 4.49 (1H, br s), 4.98 (1H, br s), 7.32 (1H, d, J=8.5 Hz), 7.76 (1H,dd, J=8.8, 2.1 Hz), 7.83 (1H, d, J=2.4 Hz).

Reference Example 77 tert-Butyl1-[(1S)-1-(4-methoxyphenyl)ethyl]-3-methyl-5-oxopyrrolidine-3-carboxylate

Step 1 1-[(1S)-1-(4-Methoxyphenyl)ethyl]-5-oxopyrrolidine-3-carboxylicacid

A mixture of (1S)-1-(4-methoxyphenyl)ethanamine (7.6 g) and itaconicacid (6.5 g) was stirred at 130° C. for 1 hour. After cooling,chloroform was added to the reaction solution. The organic layer waswashed with 1 N hydrochloric acid and saturated saline in this order andthen dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure to obtain a stereoisomeric mixture (12.7 g)related to the 3-position of the title compound.

Step 2 tert-Butyl1-[(1S)-1-(4-methoxyphenyl)ethyl]-5-oxopyrrolidine-3-carboxylate

To a tetrahydrofuran (50 ml)-tert-butanol (50 ml) mixed solution of thecompound (12.7 g) obtained in the preceding step 1, di-tert-butyldicarbonate (16.4 g) and 4-dimethylaminopyridine (1.2 g) were added, andthe mixture was stirred at room temperature for 4 hours. The reactionsolution was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (n-hexane-ethylacetate) to obtain a stereoisomeric mixture (13.9 g) related to the3-position of the title compound.

Step 3 tert-Butyl1-[(1S)-1-(4-methoxyphenyl)ethyl]-3-methyl-5-oxopyrrolidine-3-carboxylate

To a solution of the compound (13.9 g) obtained in the preceding step 2in N,N-dimethylformamide (100 ml), methyl iodide (27.1 ml) and sodiumhydride (55% oil, 7.6 g) were added, and the mixture was stirred at roomtemperature for 19 hours. Water was added to the reaction solution underice cooling, followed by extraction with ethyl acetate. The extract waswashed with water and saturated saline in this order and then dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure. The obtained residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate) to obtain low polar isomer A(3.9 g) and highly polar isomer B (5.0 g).

Low polar isomer A (Rf=0.45, n-hexane:ethyl acetate=1:1)

¹H-NMR (CDCl₃) δ: 1.17 (3H, s), 1.44 (9H, s), 1.49 (3H, d, J=7.3 Hz),2.24 (1H, d, J=16.9 Hz), 2.66 (1H, d, J=9.7 Hz), 2.90 (1H, d, J=16.9Hz), 3.61 (1H, d, J=9.7 Hz), 3.81 (3H, s), 5.46 (1H, q, J=7.1 Hz), 6.87(2H, d, J=9.1 Hz), 7.23 (2H, d, J=8.5 Hz).

Highly polar isomer B (Rf=0.35, n-hexane:ethyl acetate=1:1)

¹H-NMR (CDCl₃) δ: 1.34 (3H, s), 1.35 (9H, s), 1.49 (3H, d, J=7.3 Hz),2.26 (1H, d, J=16.9 Hz), 2.90 (1H, d, J=16.3 Hz), 3.02 (1H, d, J=9.7Hz), 3.29 (1H, d, J=9.7 Hz), 3.79 (3H, s), 5.45 (1H, q, J=7.3 Hz), 6.86(2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz).

Reference Example 78 tert-ButylN-[3-methyl-5-oxo-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-3-yl]carbamate

Step 11-[(1S)-1-(4-Methoxyphenyl)ethyl]-3-methyl-5-oxopyrrolidine-3-carboxylicacid

To a solution of the low polar isomer A (3.8 g) obtained in step 3 ofReference Example 77 in dichloromethane (50 ml), trifluoroacetic acid(10 ml) was added, and the mixture was stirred at room temperature for24 hours. Water was added to the reaction solution to separate twolayers. Then, the aqueous layer was subjected to extraction withchloroform. The organic layers were combined, washed with saturatedsaline and then dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. The obtained residue was washedwith n-hexane to obtain the title compound (2.7 g).

¹H-NMR (CDCl₃) δ: 1.25 (3H, s), 1.50 (3H, d, J=6.7 Hz), 2.36 (1H, d,J=16.9 Hz), 2.74 (1H, d, J=10.3 Hz), 3.01 (1H, d, J=16.9 Hz), 3.72 (1H,d, J=10.3 Hz), 3.81 (3H, s), 5.47 (1H, q, J=7.1 Hz), 6.88 (2H, d, J 8.5Hz), 7.22 (2H, d, J=8.5 Hz).

Step 24-Amino-1-[(1S)-1-(4-methoxyphenyl)ethyl]-4-methylpyrrolidin-2-one

To a solution of the compound (2.7 g) obtained in the preceding step 1in toluene (30 ml), triethylamine (2.7 ml) and diphenylphosphoryl azide(2.5 ml) were added, and the mixture was heated to reflux for 3 hours.After cooling, the reaction solution was concentrated under reducedpressure. 1,4-Dioxane (10 ml), water (5 ml), and concentratedhydrochloric acid (5 ml) were added to the obtained residue, and themixture was stirred at 50° C. for 2.5 hours. After cooling, water wasadded to the reaction solution, and the aqueous layer was washed withethyl acetate. The aqueous layer was made alkaline by the addition of a10 N aqueous sodium hydroxide solution, followed by extraction withchloroform. The extract was washed with saturated saline and then driedover anhydrous sodium sulfate. The solvent was distilled off underreduced pressure to obtain a crude product of the title compound, whichwas used directly in the next reaction.

¹H-NMR (CDCl₃) δ: 1.17 (3H, s), 1.50 (3H, d, J=7.3 Hz), 1.64 (2H, br s),2.37 (1H, d, J=16.3 Hz), 2.42 (1H, d, J=16.3 Hz), 2.82 (1H, d, J=9.7Hz), 3.07 (1H, d, J 9.7 Hz), 3.80 (3H, s), 5.50 (1H, q, J=7.1 Hz), 6.87(2H, d, J=8.5 Hz), 7.22 (2H, d, J=7.9 Hz).

Step 3 tert-ButylN-[1-[(1S)-1-(4-methoxyphenyl)ethyl]-3-methyl-5-oxopyrrolidin-3-yl]carbamate

To a solution of the compound obtained in the preceding step 2 inethanol (30 ml), di-tert-butyl dicarbonate (3.3 g) was added, and themixture was stirred at room temperature for 16 hours. The reactionsolution was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (n-hexane-ethylacetate) to obtain the title compound (1.2 g).

¹H-NMR (CDCl₃) δ: 1.25 (3H, s), 1.43 (9H, s), 1.49 (3H, d, J=7.9 Hz),2.34 (1H, d, J=16.3 Hz), 2.76 (1H, d, J=16.3 Hz), 2.88 (1H, d, J=9.7Hz), 3.65 (1H, d, J 9.7 Hz), 3.80 (3H, s), 4.62 (1H, br s), 5.49 (1H, q,J 7.1 Hz), 6.86 (2H, d, J=8.5 Hz), 7.22 (2H, d, J=8.5 Hz).

Step 4 tert-Butyl N-(3-methyl-5-oxopyrrolidin-3-yl)carbamate

Trifluoroacetic acid (10 ml) was added to the compound (1.2 g) obtainedin the preceding step 3, and the mixture was stirred at 80° C. for 7hours. After cooling, the reaction solution was concentrated underreduced pressure. The obtained residue was dissolved in 1,4-dioxane (20ml). To this solution, a saturated aqueous solution of sodiumbicarbonate was added to make the solution alkaline. Then, di-tert-butyldicarbonate (1.1 g) was added to the mixture, and the resulting mixturewas stirred at room temperature for 23 hours. The reaction solution wasconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (chloroform-methanol) to obtain thetitle compound (0.65 g).

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 1.50 (3H, s), 2.28 (1H, d, J=16.3 Hz),2.75 (1H, d, J=16.3 Hz), 3.30 (1H, d, J=9.7 Hz), 3.74 (1H, d, J=9.7 Hz),4.71 (1H, br s), 5.52 (1H, br s).

Step 5 tert-ButylN-[1-(4-bromophenyl)-3-methyl-5-oxopyrrolidin-3-yl]carbamate

The title compound (0.8 g) was obtained by the same procedures as instep 1 of Reference Example 72 using the compound (0.65 g) obtained inthe preceding step 4.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 1.56 (3H, s), 2.56 (1H, d, J=16.9 Hz),3.00 (1H, d, J=16.3 Hz), 3.72 (1H, d, J=10.3 Hz), 4.22 (1H, d, J=9.1Hz), 4.73 (1H, br s), 7.47 (2H, d, J=9.1 Hz), 7.51 (2H, d, J=9.1 Hz).

Step 6 tert-ButylN-[3-methyl-5-oxo-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-3-yl]carbamate

The title compound (0.65 g) was obtained by the same procedures as instep 3 of Reference Example 61 using the compound (0.8 g) obtained inthe preceding step 5.

¹H-NMR (CDCl₃) δ: 1.34 (12H, s), 1.56 (3H, s), 1.44 (9H, s), 2.58 (1H,d, J=16.9 Hz), 3.00 (1H, d, J=16.9 Hz), 3.78 (1H, d, J=10.3 Hz), 4.23(1H, d, J=10.3 Hz), 4.74 (1H, br s), 7.62 (2H, d, J=9.1 Hz), 7.80 (2H,d, J=8.5 Hz).

Reference Example 79 tert-ButylN-[3-methyl-5-oxo-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-3-yl]carbamate

Step 11-[(1S)-1-(4-Methoxyphenyl)ethyl]-3-methyl-5-oxopyrrolidine-3-carboxylicacid

The title compound (2.7 g) was obtained by the same procedures as instep 1 of Reference Example 78 using the highly polar isomer B (5.0 g)obtained in step 3 of Reference Example 77.

¹H-NMR (CDCl₃) δ: 1.42 (3H, s), 1.50 (3H, d, J=7.3 Hz), 2.36 (1H, d,J=16.9 Hz), 2.96 (1H, d, J=16.9 Hz), 3.07 (1H, d, J=10.3 Hz), 3.33 (1H,d, J=10.9 Hz), 3.78 (3H, s), 5.46 (1H, q, J=7.1 Hz), 6.84 (2H, d, J 8.5Hz), 7.19 (2H, d, J=8.5 Hz).

Step 24-Amino-1-[(1S)-1-(4-methoxyphenyl)ethyl]-4-methylpyrrolidin-2-one

A crude product of the title compound was obtained by the sameprocedures as in step 2 of Reference Example 78 using the compound (2.7g) obtained in the preceding step 1 and used directly in the nextreaction.

¹H-NMR (CDCl₃) δ: 1.31 (3H, s), 1.48 (3H, d, J=6.7 Hz), 2.32 (1H, d,J=16.9 Hz), 2.47 (1H, d, J=16.3 Hz), 2.74 (1H, d, J=9.7 Hz), 3.18 (1H,d, J=9.7 Hz), 3.80 (3H, s), 5.49 (1H, q, J=7.1 Hz), 6.87 (2H, d, J=9.1Hz), 7.24 (2H, d, J=9.1 Hz).

Step 3 tert-ButylN-[1-[(1S)-1-(4-methoxyphenyl)ethyl]-3-methyl-5-oxopyrrolidin-3-yl]carbamate

The title compound (1.0 g) was obtained by the same procedures as instep 3 of Reference Example 78 using the compound obtained in thepreceding step 2.

¹H-NMR (CDCl₃) δ: 1.35 (9H, s), 1.47 (3H, s), 1.48 (3H, d, J=6.7 Hz),2.42 (1H, d, J=16.3 Hz), 2.64 (1H, d, J=16.3 Hz), 3.18-3.30 (2H, m),3.79 (3H, s), 4.54 (1H, br s), 5.47 (1H, q, J=6.7 Hz), 6.85 (2H, d,J=8.5 Hz), 7.22 (2H, d, J=8.5 Hz).

Step 4 tert-Butyl N-(3-methyl-5-oxopyrrolidin-3-yl)carbamate

The title compound (0.4 g) was obtained by the same procedures as instep 4 of Reference Example 78 using the compound (1.0 g) obtained inthe preceding step 3.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 1.50 (3H, s), 2.28 (1H, d, J=16.3 Hz),2.75 (1H, d, J=16.3 Hz), 3.30 (1H, d, J=9.7 Hz), 3.74 (1H, d, J=9.7 Hz),4.70 (1H, br s), 5.46 (1H, br s).

Step 5 tert-ButylN-[1-(4-bromophenyl)-3-methyl-5-oxopyrrolidin-3-yl]carbamate

The title compound (0.4 g) was obtained by the same procedures as instep 1 of Reference Example 72 using the compound (0.4 g) obtained inthe preceding step 4.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 1.56 (3H, s), 2.56 (1H, d, J=16.9 Hz),3.00 (1H, d, J=16.3 Hz), 3.72 (1H, d, J=9.7 Hz), 4.22 (1H, d, J=9.1 Hz),4.73 (1H, br s), 7.47 (2H, d, J=9.1 Hz), 7.51 (2H, d, J=9.1 Hz).

Step 6 tert-ButylN-[3-methyl-5-oxo-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-3-yl]carbamate

The title compound (0.35 g) was obtained by the same procedures as instep 3 of Reference Example 61 using the compound (0.4 g) obtained inthe preceding step 5.

¹H-NMR (CDCl₃) δ: 1.34 (12H, s), 1.44 (9H, s), 1.56 (3H, s), 2.58 (1H,d, J=16.9 Hz), 3.00 (1H, d, J=16.9 Hz), 3.78 (1H, d, J=10.3 Hz), 4.23(1H, d, J=10.3 Hz), 4.73 (1H, br s), 7.62 (2H, d, J=9.1 Hz), 7.80 (2H,d, J=8.5 Hz).

The present invention will be described specifically with reference tothe Examples shown below. However, these Examples are neither intendedto limit the present invention nor be construed as being limited in anysense. In the present specification, reagents, solvents, and startingmaterials can be obtained easily from commercially available supplysources or can be produced by methods known in the art, unless otherwisespecified.

Example 1N-Benzyl-3-[4-[[(2S)-pyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2-b]pyridazin-6-amine

Step 1 N-Benzyl-3-bromoimidazo[1,2-b]pyridazin-6-amine

3-Bromo-6-chloroimidazo[1,2-b]pyridazine (20.0 g), phenylmethanamine(11.3 ml), and potassium fluoride (12.0 g) were dissolved in dimethylsulfoxide (400 ml), and the solution was stirred at 130° C. for 24hours. After standing to cool to room temperature, the reaction solutionwas poured into ice water (2.0 L). The resulting solid was collected byfiltration and dried under reduced pressure. The obtained solid wasdissolved in hot ethyl acetate, and the insoluble matter was filteredunder heating. After distilling off the solvent, the solid wasrecrystallized from ethyl acetate to obtain the title compound (21.0 g).

¹H-NMR (CDCl₃) δ: 4.61 (2H, d, J=5.2 Hz), 4.75 (1H, br s), 6.45 (1H, d,J=9.7 Hz), 7.31 (1H, td, J=6.4, 2.9 Hz), 7.36-7.39 (2H, m), 7.45 (2H, d,J=7.4 Hz), 7.49 (1H, s), 7.60 (1H, d, J=9.7 Hz).

Step 2 tert-Butyl(2S)-2-[[4-[6-(Benzylamino)imidazo[1,2-b]pyridazin-3-yl]phenoxy]methyl]pyrrolidine-1-carboxylate

1,4-Dioxane (10 ml) and water (5 ml) were added to the compound (107 mg)obtained in the preceding step 1, the compound (170 mg) obtained in step2 of Reference Example 1, sodium carbonate (56 mg), and a[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethaneadduct (29 mg), and the mixture was heated to reflux for 1 hour under anitrogen atmosphere. After cooling, water was added to the reactionsolution, followed by extraction with ethyl acetate. The extract waswashed with saturated saline and then dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure. Theobtained residue was purified by silica gel column chromatography (ethylacetate) to obtain the title compound (65 mg).

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 1.81-2.13 (4H, m), 3.29-3.51 (2H, m),3.75-4.02 (1H, m), 4.09-4.26 (2H, m), 4.59 (2H, d, J=5.0 Hz), 6.46 (1H,d, J=10.1 Hz), 6.98 (2H, d, J=7.3 Hz), 7.28-7.44 (5H, m), 7.65-7.73 (2H,m), 7.88 (2H, br s).

Step 3N-Benzyl-3-[4-[[(2S)-pyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2-b]pyridazin-6-amine

To a solution of the compound (65 mg) obtained in the preceding step 2in dichloromethane (5 ml), trifluoroacetic acid (1 ml) was added, andthe mixture was stirred at room temperature for 2.5 hours. A saturatedaqueous solution of sodium bicarbonate was added to the reactionsolution, followed by extraction with chloroform. The extract was washedwith saturated saline and then dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure. The obtained residuewas purified by silica gel column chromatography (basic silica gel,chloroform-methanol) to obtain the title compound (40 mg).

¹H-NMR (CDCl₃) δ: 1.70-2.02 (3H, m), 2.91-3.09 (2H, m), 3.48-3.59 (1H,m), 3.87-4.00 (2H, m), 4.59 (2H, d, J=5.0 Hz), 4.69 (1H, br s), 6.46(1H, d, J=9.6 Hz), 6.95 (2H, d, J=7.8 Hz), 7.29-7.44 (5H, m), 7.68 (1H,d, J=9.6 Hz), 7.71 (1H, s), 7.87 (2H, d, J=7.8 Hz).

The following compounds were obtained by the same procedures as inExample 1 with the compound obtained in step 1 of Example 1 as thestarting material using the compounds obtained in the Reference Examples(the column “Reference Example” represents Reference Example No. of eachcompound used in the synthesis of the compound of the correspondingExample).

TABLE 9 Reference Example Example Structure and name Instrumental data 22

¹H-NMR (CDCl₃) δ: 1.47-1.94 (4H, m), 2.87-3.02 (2H, m), 3.89 (1H, t, J =8.0 Hz), 3.96 (1H, dd, J = 8.6, 5.2 Hz), 4.62 (2H, d, J = 5.2 Hz),4.64-4.73 (1H, m), 6.48 (1H, d, J = 9.7 Hz), 6.88 (1H, dd, J = 8.0, 4.0Hz), 7.28-7.44 (6H, m), 7.58 (1H, d, J = 8.0 Hz), 7.70 (1H, d, J = 9.7Hz), 7.76 (1H, br s), 7.81 (1H, s). N-Benzyl-3-[3-[[(2S)-pyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2- b]pyridazin-6-amine 3 3

¹H-NMR (CDCl₃) δ: 2.00-2.21 (2H, m), 2.98-3.32 (4H, m), 4.59 (2H, d, J =5.5 Hz), 4.71 (1H, t, J = 5.0 Hz), 4.91 (1H, t, J = 5.3 Hz), 6.47 (1H,d, J = 9.6 Hz), 6.90 (2H, d, J = 8.7 Hz), 7.29-7.43 (5H, m), 7.69 (1H,d, J = 9.6 Hz), 7.71 (1H, s), 7.87 (2H, d, J = 9.2 Hz). ESI-MS (m/z):386 (M + H)⁺. N-Benzyl-3-[4-[(3R)-pyrrolidin-3-yl]oxyphenyl]imidazo[1,2- b]pyridazin-6-amine 4 4

¹H-NMR (CDCl₃) δ: 1.92-2.08 (2H, m), 2.82-2.90 (1H, m), 2.95 (1H, dd, J= 12.8, 4.6 Hz), 3.12-3.23 (2H, m), 4.63 (2H, d, J = 5.0 Hz), 4.70 (1H,t, J = 5.0 Hz), 4.80-4.86 (1H, m), 6.49 (1H, d, J = 9.6 Hz), 6.83 (1H,dd, J = 8.5, 2.5 Hz), 7.27-7.42 (6H, m), 7.56 (1H, d, J = 7.8 Hz), 7.64(1H, t, J = 2.1 Hz), 7.71 (1H, d, J = 9.6 Hz), 7.80 (1H, s).N-Benzyl-3-[3-[(3R)-pyrrolidin-3- yl]oxyphenyl]imidazo[1,2-b]pyridazin-6-amine 5 5

¹H-NMR (CDCl₃) δ: 2.01-2.12 (2H, m), 2.61-2.73 (1H, m), 2.93 (1H, dd, J= 11.5, 6.0 Hz), 2.99-3.17 (2H, m), 3.23 (1H, dd, J = 11.5, 8.7 Hz),3.93 (1H, dd, J = 10.1, 7.3 Hz), 3.99 (1H, dd, J = 9.2, 6.0 Hz), 4.59(2H, t, J = 5.0 Hz), 4.68 (1H, br s), 6.47 (1H, d, J = 10.1 Hz), 6.93(2H, d, J = 8.7 Hz), 7.26-7.43 (5H, m), 7.70 (1H, d, J = 10.1 Hz), 7.72(1H, s), 7.89 (2H, d, J = 8.7 Hz). N-Benzyl-3-[4-[[(3R)-pyrrolidin-3-yl]methoxy]phenyl]imidazo[1,2- b]pyridazin-6-amine

Example 6N-Benzyl-3-[4-[2-[(2S)-pyrrolidin-2-yl]ethoxy]phenyl]imidazo[1,2-b]pyridazin-6-amine

Step 1N-Benzyl-3-[4-[tert-butyldimethylsilyl]oxyphenyl]imidazo[1,2-b]pyridazin-6-amine

The title compound (634 mg) was obtained by the same procedures as instep 2 of Example 1 with the compound (606 mg) obtained in step 1 ofExample 1 as the starting material using[4-[t-butyldimethylsilyl]oxyphenyl]boronic acid (327 mg).

¹H-NMR (CDCl₃) δ: 0.24 (6H, s), 1.01 (9H, s), 4.59 (2H, d, J=5.2 Hz),4.70 (1H, t, J=5.2 Hz), 6.46 (1H, d, J=9.7 Hz), 6.86-6.89 (2H, m),7.29-7.33 (1H, m), 7.36-7.39 (2H, m), 7.40-7.43 (2H, m), 7.68 (1H, d,J=9.7 Hz), 7.72 (1H, s), 7.83-7.86 (2H, m).

ESI-MS (m/z): 431 (M+H)⁺.

Step 2 4-[6-(Benzylamino)imidazo[1,2-b]pyridazin-3-yl]phenol

The compound (634 mg) obtained in the preceding step 1 was dissolved intetrahydrofuran (5 ml). To the solution, tetrabutylammonium fluoride(1.0 M solution in tetrahydrofuran, 1.5 ml) was added, and the mixturewas stirred at room temperature for 30 minutes. Ethyl acetate and waterwere added to the reaction solution to separate the aqueous and organiclayers. The organic layer was washed with saturated saline, dried overanhydrous sodium sulfate and then concentrated under reduced pressure.Ethyl acetate and n-hexane were added to the obtained residue, and thesolid was collected by filtration to obtain the title compound (439 mg).

¹H-NMR (DMSO-d₆) δ: 4.47 (2H, d, J=5.5 Hz), 6.73 (1H, d, J=9.6 Hz),6.75-6.79 (2H, m), 7.23-7.27 (1H, m), 7.33-7.37 (2H, m), 7.39-7.43 (2H,m), 7.61 (1H, t, J=5.5 Hz), 7.67 (1H, s), 7.73 (1H, d, J=9.6 Hz),7.75-7.78 (2H, m), 9.54 (1H, s).

ESI-MS (m/z): 317 (M+H)⁺.

Step 3 tert-Butyl(2S)-2-[2-[4-[6-(Benzylamino)imidazo[1,2-b]pyridazin-3-yl]phenoxy]ethyl]pyrrolidine-1-carboxylate

Diisopropylethylamine (575 μl) was added to a solution of2-[(2S)-1-tert-butoxycarbonylpyrrolidin-2-yl]acetic acid (688 mg) intetrahydrofuran (15 ml, and the mixture was cooled to −20° C. Isobutylchloroformate (428 μl) was added thereto, and the mixture was stirred at−20° C. for 45 minutes. The resulting solid was filtered off, and thesolid was washed with tetrahydrofuran. Sodium borohydride (227 mg) wasadded to the filtrate, and the mixture was stirred at room temperaturefor 5 minutes. Then, methanol (5 ml) was added thereto, and the mixturewas stirred at room temperature for 5 minutes. Ethyl acetate and waterwere added to the reaction solution to separate the aqueous and organiclayers. The aqueous layer was subjected to extraction with ethylacetate. The organic layers were combined, dried over anhydrous sodiumsulfate and then concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (n-hexane-ethylacetate) to obtain tert-butyl(2S)-2-(2-hydroxyethyl)pyrrolidine-1-carboxylate (606 mg).

The compound (150 mg) obtained in the preceding step 2, tert-butyl(2S)-2-(2-hydroxyethyl)pyrrolidine-1-carboxylate (153 mg), andcyanomethylene tributylphosphorane (172 mg) were suspended in toluene (8ml), and the suspension was heated to reflux for 45 minutes.Cyanomethylene tributylphosphorane (86 mg) was further added thereto,and the mixture was further heated to reflux for 1 hour. The solvent wasdistilled off under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (dichloromethane-methanol) to obtainthe title compound as a crude product, which was used directly in thenext reaction.

ESI-MS (m/z): 514 (M+H)⁺.

Step 4N-Benzyl-3-[4-[2-[(2S)-pyrrolidin-2-yl]ethoxy]phenyl]imidazo[1,2-b]pyridazin-6-amine

The crude product obtained in the preceding step 3 was dissolved indichloromethane (5 ml). To the solution, a solution of 4 N hydrochloricacid in dioxane (5 ml) was added, and the mixture was stirred at roomtemperature for 1 hour. The solvent was distilled off under reducedpressure. A saturated aqueous solution of sodium bicarbonate anddichloromethane were added to the residue to separate the aqueous andorganic layers. The organic layer was dried over anhydrous sodiumsulfate and then concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (basic silicagel, dichloromethane-methanol). Diethyl ether was added to the residue,and the solid was collected by filtration to obtain the title compound(110 mg).

¹H-NMR (CDCl₃) δ: 1.33-1.41 (1H, m), 1.71-1.83 (2H, m), 1.91-2.01 (3H,m), 2.86-2.91 (1H, m), 3.00-3.05 (1H, m), 3.21-3.27 (1H, m), 4.12 (2H,td, J=6.3, 1.7 Hz), 4.59 (2H, d, J=5.4 Hz), 4.74 (1H, t, J=5.4 Hz), 6.46(1H, d, J=9.7 Hz), 6.92-6.96 (2H, m), 7.30-7.33 (1H, m), 7.36-7.42 (4H,m), 7.68 (1H, d, J=9.7 Hz), 7.71 (1H, s), 7.86-7.89 (2H, m).

ESI-MS (m/z): 414 (M+H)⁺.

Example 72-[(2S)-2-[[3-[6-(Benzylamino)imidazo[1,2-b]pyridazin-3-yl]phenoxy]methyl]pyrrolidin-1-yl]ethanol

Step 12-[(2S)-2-[[3-[6-(Benzylamino)imidazo[1,2-b]pyridazin-3-yl]phenoxy]methyl]pyrrolidin-1-yl]ethanol

To a solution of the compound (100 mg) obtained in Example 2 indichloromethane (5 ml), triethylamine (0.07 ml) and 2-iodoethanol (0.024ml) were added, and the mixture was stirred at room temperature for 4hours and then heated to reflux for 7 hours. Triethylamine (0.07 ml) and2-iodoethanol (0.024 ml) were further added to the reaction solution,and the mixture was further heated to reflux for 2 hours. After cooling,water was added to the reaction solution, followed by extraction withethyl acetate. The extract was washed with saturated saline and thendried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure. The obtained residue was purified by silica gel columnchromatography (basic silica gel, chloroform-methanol) to obtain thetitle compound (55 mg).

¹H-NMR (CDCl₃) δ: 1.62-1.81 (3H, m), 1.94-2.05 (1H, m), 2.34 (1H, q,J=8.3 Hz), 2.60 (1H, dt, J=12.7, 3.6 Hz), 2.80 (1H, br s), 2.97-3.18(3H, m), 3.52-3.65 (2H, m), 3.86 (1H, dd, J=8.9, 6.2 Hz), 3.96 (1H, dd,J=8.7, 5.5 Hz), 4.61 (2H, d, J=5.5 Hz), 4.74 (1H, br s), 6.48 (1H, d,J=9.6 Hz), 6.87 (1H, d, J=9.2 Hz), 7.27-7.44 (5H, m), 7.56 (1H, d, J=7.8Hz), 7.70 (1H, dd, J=9.4, 1.1 Hz), 7.80 (1H, br s), 7.82 (1H, s).

ESI-MS (m/z): 444 (M+H)⁺.

Example 8N-Benzyl-3-[3-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2-b]pyridazin-6-amine

Step 1N-Benzyl-3-[3-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2-b]pyridazin-6-amine

To a solution of the compound (90 mg) obtained in Example 2 intetrahydrofuran (10 ml), a 35% aqueous formaldehyde solution (1 ml) andsodium triacetoxyborohydride (72 mg) were added, and the mixture wasstirred at room temperature for 2.5 hours. A saturated aqueous solutionof sodium bicarbonate was added to the reaction solution, followed byextraction with ethyl acetate. The extract was washed with saturatedsaline and then dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (basic silica gel,chloroform-methanol) to obtain the title compound (65 mg).

¹H-NMR (CDCl₃) δ: 1.64-1.83 (3H, m), 1.95-2.05 (1H, m), 2.27 (1H, td,J=9.6, 7.3 Hz), 2.44 (3H, s), 2.60-2.67 (1H, m), 3.07 (1H, t, J=8.9 Hz),3.94 (1H, dd, J=9.2, 5.7 Hz), 4.03 (1H, dd, J=9.2, 5.7 Hz), 4.61 (2H, d,J=5.2 Hz), 4.68 (1H, t, J=5.2 Hz), 6.47 (1H, d, J=9.7 Hz), 6.88 (1H, dd,J=8.0, 3.4 Hz), 7.29-7.33 (2H, m), 7.37 (2H, t, J=7.4 Hz), 7.42 (2H, d,J=7.4 Hz), 7.58 (1H, dd, J=6.9, 1.7 Hz), 7.69 (1H, d, J=9.2 Hz), 7.76(1H, t, J=2.0 Hz), 7.81 (1H, s).

ESI-MS (m/z): 414 (M+H)⁺.

Example 9N-[(3-Fluorophenyl)methyl]-N-methyl-3-[4-[(3R)-pyrrolidin-3-yl]oxyphenyl]imidazo[1,2-b]pyridazin-6-amine

Step 13-Bromo-N-[(3-fluorophenyl)methyl]-N-methylimidazo[1,2-b]pyridazin-6-amine

The title compound (4.04 g) was obtained by the same procedures as instep 1 of Example 1 using 1-(3-fluorophenyl)-N-methyl-methanamineinstead of phenylmethanamine.

¹H-NMR (CDCl₃) δ: 3.20 (3H, s), 4.76 (2H, s), 6.72 (1H, d, J=9.7 Hz),6.95-7.00 (1H, m), 7.03-7.06 (1H, m), 7.10-7.11 (1H, m), 7.28-7.34 (1H,m), 7.53 (1H, s), 7.66 (1H, d, J=9.7 Hz).

Step 2 tert-Butyl(3R)-3-[4-[6-[(3-fluorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenoxy]pyrrolidine-1-carboxylate

The title compound (276 mg) was obtained by the same procedures as instep 2 of Example 1 using the compound (250 mg) obtained in thepreceding step 1 and the compound (371 mg) obtained in Reference Example3.

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.10-2.23 (2H, m), 3.49-3.67 (4H, m),4.74 (2H, s), 4.93 (1H, br s), 6.75 (1H, d, J=9.7 Hz), 6.90 (2H, d,J=8.6 Hz), 6.95-7.01 (2H, m), 7.04-7.06 (1H, m), 7.29-7.34 (1H, m), 7.75(2H, d, J=10.3 Hz), 7.87-7.91 (2H, m).

Step 3N-[(3-Fluorophenyl)methyl]-N-methyl-3-[4-[(3R)-pyrrolidin-3-yl]oxyphenyl]imidazo[1,2-b]pyridazin-6-amine

The title compound (241 mg) was obtained by the same procedures as instep 3 of Example 1 with the compound (276 mg) obtained in the precedingstep 2 as the starting material.

¹H-NMR (CDCl₃) δ: 1.94-2.06 (1H, m), 2.09-2.16 (1H, m), 2.74-2.95 (2H,m), 3.02-3.22 (2H, m), 3.23 (3H, s), 4.74 (2H, s), 4.83-4.89 (1H, m),6.72-6.75 (1H, m), 6.86-6.90 (2H, m), 6.95-6.99 (2H, m), 7.04-7.06 (1H,m), 7.27-7.33 (1H, m), 7.74-7.76 (2H, m), 7.88 (2H, d, J=9.2 Hz).

The following compound was obtained by the same procedures as in Example9 with the compound obtained in step 1 of Example 9 as the startingmaterial using the compound obtained in the Reference Example.

TABLE 10 Reference Example Example Structure and name Instrumental data10 1

¹H-NMR (CDCl₃) δ: 1.54-1.61 (1H, m), 1.72-1.87 (2H, m), 1.93-1.99 (1H,m), 2.93-2.98 (1H, m), 3.02-3.07 (1H, m), 3.22 (3H, s), 3.50-3.56 (1H,m), 3.90 (1H, dd, J = 9.2, 6.9 Hz), 3.97 (1H, dd, J = 9.2, 5.2 Hz), 4.73(2H, s), 6.73 (1H, d, J = 9.7 Hz), 6.92-6.98 (4H, m), 7.03- 7.06 (1H,m), 7.28-7.34 (1H, m), 7.72- 7.76 (2H, m), 7.89 (2H, d, J = 8.6 Hz).N-[(3-Fluorophenyl)methyl]-N- methyl-3-[4-[[(2S)-pyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2- b]pyridazin-6-amine

Example 116-[(3-Fluorophenyl)methoxy]-3-[4-[[(2R)-pyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2-b]pyridazine

Step 1 3-Bromo-6-[(3-fluorophenyl)methoxy]imidazo[1,2-b]pyridazine

To a solution of 3-fluorobenzyl alcohol (0.59 g) inN,N-dimethylformamide (20 ml), sodium hydride (55% oil, 0.26 g) wasadded under ice cooling, and the mixture was stirred at the sametemperature as above for 10 minutes.3-Bromo-6-chloroimidazo[1,2-b]pyridazine (1 g) was added to the reactionsolution, and the mixture was stirred at the same temperature as abovefor 1 hour. A saturated aqueous solution of ammonium chloride was addedto the reaction solution, followed by extraction with ethyl acetate. Theextract was washed with water and saturated saline in this order andthen dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure. The obtained residue was washed with n-hexane toobtain the title compound (1.2 g).

¹H-NMR (CDCl₃) δ: 5.45 (2H, s), 6.78 (1H, d, J=9.6 Hz), 7.02-7.08 (1H,m), 7.25-7.40 (3H, m), 7.61 (1H, s), 7.79 (1H, d, J=9.6 Hz).

Step 2 tert-Butyl(2R)-2-[[4-[6-[(3-fluorophenyl)methoxy]imidazo[1,2-b]pyridazin-3-yl]phenoxy]methyl]pyrrolidine-1-carboxylate

1,4-Dioxane (10 ml) and water (5 ml) were added to the compound (0.26 g)obtained in the preceding step 1, the compound (0.4 g) obtained inReference Example 6, sodium carbonate (0.13 g), and a[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethaneadduct (68 mg), and the mixture was heated to reflux for 1.5 hours undera nitrogen atmosphere. After cooling, water was added to the reactionsolution, and the mixture was subjected to extraction with ethylacetate. The extract was washed with saturated saline and then driedover anhydrous sodium sulfate. The solvent was distilled off underreduced pressure. The obtained residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate) to obtain the title compound(0.35 g).

¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 1.85-2.13 (4H, m), 3.32-3.49 (2H, br m),3.83-4.03 (1H, br m), 4.14-4.29 (2H, m), 5.40 (2H, s), 6.77 (1H, d,J=9.6 Hz), 7.00-7.06 (3H, m), 7.19 (1H, d, J=9.6 Hz), 7.25 (1H, d, J=8.3Hz), 7.34-7.41 (1H, m), 7.79-7.89 (4H, m).

Step 36-[(3-Fluorophenyl)methoxy]-3-[4-[[(2R)-pyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2-b]pyridazine

To a solution of the compound (0.35 g) obtained in the preceding step 2in dichloromethane (10 ml), trifluoroacetic acid (3 ml) was added, andthe mixture was stirred at room temperature for 5 hours. A saturatedaqueous solution of sodium bicarbonate was added to the reactionsolution, followed by extraction with chloroform. The extract was washedwith saturated saline and then dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure. Ethyl acetate wasadded to the obtained residue, and the deposits were collected byfiltration to obtain the title compound (65 mg).

¹H-NMR (CDCl₃) δ: 1.83-2.21 (5H, m), 3.23-3.36 (2H, m), 3.84-3.92 (1H,m), 4.21-4.25 (2H, m), 5.35 (2H, s), 6.76 (1H, d, J=9.6 Hz), 7.00-7.06(3H, m), 7.17 (1H, d, J=9.6 Hz), 7.23 (1H, d, J=7.8 Hz), 7.37 (1H, td,J=7.9, 5.8 Hz), 7.76 (1H, s), 7.81 (2H, d, J=9.5 Hz), 7.86 (1H, d, J=9.6Hz).

The following compounds were obtained by the same procedures as inExample 11 with the compound obtained in step 1 of Example 11 as thestarting material using the compounds obtained in the ReferenceExamples.

TABLE 11 Reference Example Example No. No. Structure and nameInstrumental data 12 1

¹H-NMR (CDCl₃) δ: 1.69-2.12 (5H, m), 3.06-3.21 (2H, m), 3.66-3.74 (1H,m), 4.03-4.13 (2H, m), 5.38 (2H, s), 6.77 (1H, d, J = 9.6 Hz), 7.00-7.06(3H, m), 7.18 (1H, d, J = 9.6 Hz), 7.24 (1H, d, J = 7.8 Hz), 7.37 (1H,td, J = 7.9, 5.8 Hz), 7.79 (1H, s), 7.82 (2H, d, J = 9.5 Hz), 7.86 (1H,d, J = 9.6 Hz). 6-[(3-Fluorophenyl)methoxy]-3- [4-[[(2S)-pyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2- b]pyridazine 13 3

¹H-NMR (CDCl₃) δ: 1.78 (1H, br s), 2.02-2.21 (2H, m), 2.96-3.03 (1H, m),3.12 (1H, dd, J = 12.4, 4.6 Hz), 3.20- 3.31 (2H, m), 4.93 (1H, t, J =5.3 Hz), 5.40 (2H, s), 6.78 (1H, d, J = 9.6 Hz), 6.97 (2H, d, J = 9.2Hz), 7.05 (1H, td, J = 8.5, 2.0 Hz), 7.19 (1H, d, J = 9.2 Hz), 7.24 (1H,d, J = 7.3 Hz), 7.37 (1H, td, J = 8.0, 6.0 Hz), 7.81 (1H, s), 7.83 (2H,d, J = 8.3 Hz), 7.87 (1H, d, J = 9.2 Hz). 6-[(3-Fluorophenyl)methoxy]-3-[4-[(3R)-pyrrolidin-3- yl]oxyphenyl]imidazo[1,2- b]pyridazine 14 7

¹H-NMR (CDCl₃) δ: 1.60 (2H, br s), 3.14 (2H, t, J = 5.0 Hz), 4.08 (2H,t, J = 4.6 Hz), 5.40 (2H, s), 6.78 (1H, d, J = 9.6 Hz), 7.00-7.07 (3H,m), 7.19 (1H, d, J = 9.6 Hz), 7.24 (1H, d, J = 7.8 Hz), 7.38 (1H, td, J= 7.9, 5.8 Hz), 7.81 (1H, s), 7.84 (2H, d, J = 8.7 Hz), 7.87 (1H, d, J =9.6 Hz). 2-[4-[6-[(3- Fluorophenyl)methoxy]imidazo[1,2- b]pyridazin-3-yl]phenoxy]ethanamine

Example 156-[(1R)-1-(3-Fluorophenyl)ethoxy]-3-[4-(4-piperidyloxy)phenyl]imidazo[1,2-b]pyridazine

Step 1 3-Bromo-6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazine

The title compound (3.3 g) was obtained by the same procedures as instep 1 of Example 11 using (1R)-1-(3-fluorophenyl)ethanol (1.54 g)instead of 3-fluorobenzyl alcohol.

¹H-NMR (CDCl₃) δ: 1.72 (3H, d, J=6.4 Hz), 6.12 (1H, q, J=6.4 Hz), 6.73(1H, d, J=10.1 Hz), 6.93-7.01 (1H, m), 7.22-7.34 (3H, m), 7.55 (1H, s),7.74 (1H, d, J=9.2 Hz).

Step 2 tert-Butyl4-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenoxy]piperidine-1-carboxylate

1,4-Dioxane (10 ml) and water (5 ml) were added to the compound (200 mg)obtained in the preceding step 1, the compound (290 mg) obtained inReference Example 8, sodium carbonate (73 mg), and a[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethaneadduct (49 mg), and the mixture was heated to reflux for 1 hour under anitrogen atmosphere. After cooling, water was added to the reactionsolution, and the mixture was subjected to extraction with ethylacetate. The extract was washed with saturated saline and then driedover anhydrous sodium sulfate. The solvent was distilled off underreduced pressure. The obtained residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate) to obtain the title compound(240 mg).

¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 1.68 (3H, d, J=6.4 Hz), 1.76-1.88 (2H,br m), 1.94-2.04 (2H, m), 3.35-3.43 (2H, m), 3.72-3.80 (2H, m),4.53-4.59 (1H, m), 5.92 (1H, q, J=6.6 Hz), 6.76 (1H, d, J=9.6 Hz),6.95-7.02 (3H, m), 7.13 (1H, dt, J=9.6, 1.8 Hz), 7.20 (1H, d, J=7.8 Hz),7.34 (1H, td, J=7.8, 6.0 Hz), 7.62 (2H, d, J=8.7 Hz), 7.74 (1H, s), 7.83(1H, d, J=9.6 Hz).

Step 36-[(1R)-1-(3-Fluorophenyl)ethoxy]-3-[4-(4-piperidyloxy)phenyl]imidazo[1,2-b]pyridazine

To a solution of the compound (240 mg) obtained in the preceding step 2in dichloromethane (10 ml), trifluoroacetic acid (2 ml) was added, andthe mixture was stirred at room temperature for 4 hours. A saturatedaqueous solution of sodium bicarbonate was added to the reactionsolution, followed by extraction with chloroform. The extract was washedwith saturated saline and then dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure. Ethyl acetate wasadded to the obtained residue, and the deposits were collected byfiltration to obtain the title compound (20 mg).

¹H-NMR (CDCl₃) δ: 1.68 (3H, d, J=6.4 Hz), 1.85 (1H, br s), 2.08-2.18(2H, br m), 2.25-2.35 (2H, br m), 3.19-3.28 (2H, m), 3.40 (2H, t, J=10.3Hz), 4.70 (1H, br s), 5.91 (1H, q, J=6.9 Hz), 6.78 (1H, d, J=10.1 Hz),6.94-7.02 (3H, m), 7.12 (1H, d, J=9.2 Hz), 7.21 (1H, d, J=7.8 Hz),7.31-7.39 (1H, m), 7.63 (2H, d, J=8.3 Hz), 7.74 (1H, s), 7.84 (1H, d,J=9.6 Hz).

The following compounds were obtained by the same procedures as inExample 15 with the compound obtained in step 1 of Example 15 as thestarting material using the compounds obtained in the ReferenceExamples.

TABLE 12 Reference Example Example Structure and name Instrumental data16  1

¹H-NMR (CDCl₃) δ: 1.58-2.04 (5H, m), 1.67 (3H, d, J = 6.9 Hz), 2.96-3.12 (2H, m), 3.55-3.62 (1H, m), 3.95 (1H, dd, J = 9.2, 6.9 Hz), 4.02(1H, dd, J = 9.2, 5.0 Hz), 5.93 (1H, q, J = 6.7 Hz), 6.76 (1H, d, J =9.2 Hz), 6.95-7.01 (3H, m), 7.14 (1H, d, J = 9.6 Hz), 7.20 (1H, d, J =7.8 Hz), 7.30-7.39 (1H, m), 7.62 (2H, d, J = 9.3 Hz), 7.73 (1H, s), 7.83(1H, d, J = 9.6 Hz). 6-[(1R)-1-(3-Fluorophenyl)ethoxy]-3-[4-[[(2S)-pyrrolidin-2- yl]methoxy]phenyl]imidazo[1,2- b]pyridazine 1725

¹H-NMR (CDCl₃) δ: 1.68 (3H, d, J = 6.3 Hz), 1.88 (2H, q, J = 11.8 Hz),2.11-2.19 (3H, m), 2.98 (2H, dd, J = 12.9, 10.6 Hz), 3.61 (2H, d, J =12.6 Hz), 3.95 (2H, d, J = 5.7 Hz), 5.92 (1H, q, J = 6.7 Hz), 6.77 (1H,d, J = 9.7 Hz), 6.93-7.01 (3H, m), 7.13 (1H, dt, J = 9.5, 1.7 Hz), 7.21(1H, d, J = 7.4 Hz), 7.35 (1H, td, J = 8.0, 5.7 Hz), 7.61-7.63 (2H, m),7.74 (1H, s), 7.84 (1H, d, J = 9.7 Hz). ESI-MS (m/z): 447 (M + H)⁺.6-[(1R)-1-(3-Fluorophenyl)ethoxy]-3- [4-(4-piperidylmethoxy)phenyl]imidazo[1,2- b]pyridazine

Example 183-[4-[[(2S)-Azetidin-2-yl]methoxy]phenyl]-6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazinehydrochloride

Step 1 tert-Butyl(2S)-2-[[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenoxy]methyl]azetidine-1-carboxylate

1,4-Dioxane (20 ml) and water (10 ml) were added to the compound (0.8 g)obtained in step 1 of Example 15, the compound (1.1 g) obtained inReference Example 26, sodium carbonate (0.38 g), and a[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethaneadduct (0.19 g), and the mixture was heated to reflux for 40 minutesunder a nitrogen atmosphere. After cooling, water was added to thereaction solution, and the mixture was subjected to extraction withethyl acetate. The extract was washed with saturated saline and thendried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure. The obtained residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate) to obtain the title compound(0.85 g).

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.68 (3H, d, J=6.0 Hz), 3.89-3.99 (2H,m), 3.89-3.99 (2H, m), 4.20 (1H, dd, J=10.0, 2.7 Hz), 4.34 (1H, br s),4.52-4.61 (1H, m), 5.94 (1H, q, J=6.7 Hz), 6.76 (1H, d, J=9.7 Hz),6.95-7.03 (3H, m), 7.14 (1H, dt, J=9.7, 2.1 Hz), 7.21 (1H, d, J=7.3 Hz),7.35 (1H, td, J=8.0, 5.8 Hz), 7.64 (2H, d, J=9.7 Hz), 7.75 (1H, s), 7.83(1H, d, J=9.7 Hz).

Step 23-[4-[[(2S)-Azetidin-2-yl]methoxy]phenyl]-6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazinehydrochloride

To a solution of the compound (0.85 g) obtained in the preceding step 1in dichloromethane (10 ml), trifluoroacetic acid (3 ml) was added, andthe mixture was stirred at room temperature for 2 hours. A saturatedaqueous solution of sodium bicarbonate was added to the reactionsolution, followed by extraction with chloroform. The extract was washedwith saturated saline and then dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure. A solution of 2 Nhydrochloric acid in ethanol (5 ml) was added to the obtained residue,and the mixture was concentrated under reduced pressure. The obtainedresidue was dissolved in ethanol. To the solution, ethyl acetate wasadded, and the deposits were collected by filtration to obtain the titlecompound (0.61 g).

¹H-NMR (DMSO-d₆) δ: 1.68 (3H, d, J=6.7 Hz), 2.37-2.60 (2H, m), 3.88-4.01(3H, m), 4.35 (1H, dd, J=10.9, 3.6 Hz), 4.45-4.54 (1H, m), 4.77 (1H, brs), 6.04 (1H, q, J=6.4 Hz), 7.11-7.17 (3H, m), 7.34 (2H, d, J=7.9 Hz),7.40 (1H, d, J=9.7 Hz), 7.43-7.50 (1H, m), 7.85 (2H, d, J=8.5 Hz), 8.32(1H, d, J=10.3 Hz), 8.38 (1H, s), 9.34 (1H, br s), 9.52 (1H, br s).

ESI-MS (m/z): 419 (M+H)⁺.

Example 19N-[(1R)-1-Phenylethyl]-3-[4-[[(2S)-pyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2-b]pyridazin-6-amine

Step 1 3-Bromo-N-[(1R)-1-phenylethyl]imidazo[1,2-b]pyridazin-6-amine

The title compound (1.07 g) was obtained by the same procedures as instep 1 of Example 1 using (1R)-1-phenylethanamine (0.71 ml) instead ofphenylmethanamine.

¹H-NMR (CDCl₃) δ: 1.62 (3H, s), 4.83 (1H, d, J=6.3 Hz), 5.01-5.07 (1H,m), 6.40 (1H, t, J=4.6 Hz), 7.27 (1H, tt, J=7.4, 1.6 Hz), 7.35 (2H, td,J=7.7, 3.2 Hz), 7.45 (3H, td, J=4.6, 2.1 Hz), 7.55 (1H, d, J=9.7 Hz).

Step 2 tert-Butyl(2S)-2-[[4-[6-[[(1R)-1-phenylethyl]amino]imidazo[1,2-b]pyridazin-3-yl]phenoxy]methyl]pyrrolidine-1-carboxylate

1,4-Dioxane (20 ml) and water (10 ml) were added to the compound (0.72g) obtained in the preceding step 1, the compound (1.1 g) obtained instep 2 of Reference Example 1, sodium carbonate (0.36 g), and a[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethaneadduct (185 mg), and the mixture was heated to reflux for 2 hours undera nitrogen atmosphere. After cooling, water was added to the reactionsolution, and the mixture was subjected to extraction with chloroform.The extract was washed with saturated saline and then dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure. The obtained residue was purified by silica gel columnchromatography (n-hexane-ethyl acetate) to obtain the title compound(0.85 g).

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 1.59 (3H, d, J=6.0 Hz), 1.87-2.12 (4H,m), 3.42-3.45 (2H, m), 3.78-4.27 (3H, m), 4.68 (1H, d, J=5.4 Hz), 4.96(1H, q, J=6.3 Hz), 6.45 (1H, d, J=10.3 Hz), 6.89-6.98 (2H, m), 7.22-7.44(5H, m), 7.62-7.71 (4H, m).

Step 3N-[(1R)-1-Phenylethyl]-3-[4-[[(2S)-pyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2-b]pyridazin-6-amine

To a solution of the compound (0.85 g) obtained in the preceding step 2in dichloromethane (10 ml), trifluoroacetic acid (3 ml) was added, andthe mixture was stirred at room temperature for 1.5 hours. A saturatedaqueous solution of sodium bicarbonate was added to the reactionsolution, followed by extraction with chloroform. The extract was washedwith saturated saline and then dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure. Chloroform was addedto the obtained residue, and the deposits were collected by filtrationto obtain the title compound (0.3 g).

¹H-NMR (CDCl₃) δ: 1.49 (3H, d, J=6.7 Hz), 1.74-1.83 (1H, m), 1.88-2.05(2H, m), 2.12-2.20 (1H, m), 3.17-3.35 (3H, m), 3.88-3.98 (1H, m), 4.18(1H, br s), 4.32 (1H, dd, J=10.9, 3.6 Hz), 4.80-4.88 (1H, m), 6.78 (1H,d, J=9.1 Hz), 6.99 (2H, d, J=9.1 Hz), 7.21 (1H, t, J=7.9 Hz), 7.36 (2H,t, J=7.6 Hz), 7.43 (2H, d, J=6.7 Hz), 7.65 (1H, br s), 7.74 (2H, t,J=4.8 Hz), 7.83 (2H, d, J=9.1 Hz).

ESI-MS (m/z): 414 (M+H)⁺.

The following compound was obtained by the same procedures as in Example19 with the compound obtained in step 1 of Example 19 as the startingmaterial using the compound obtained in the Reference Example.

TABLE 13 Reference Example Example Structure and name Instrumental data20 51

¹H-NMR (CDCl₃) δ: 1.47-1.57 (1H, m), 1.59 (3H, d, J = 6.7 Hz), 1.71-2.03 (4H, m), 2.89-2.96 (1H, m), 3.01-3.12 (3H, m), 3.31-3.38 (1H, m),4.73 (1H, d, J = 5.4 Hz), 4.92-4.99 (1H, m), 6.48 (1H, d, J = 9.7 Hz),7.26-7.44 (7H, m), 7.66 (1H, d, J = 9.1 Hz), 7.69 (2H, d, J = 8.5 Hz),7.72 (1H, s). ESI-MS (m/z): 431 (M + H)⁺.N-[(1R)-1-Phenylethyl]-3-[4-[[(2S)- pyrrolidin-2-yl]methylsulfanyl]phenyl]imidazo[1,2- b]pyridazin-6-amine

Example 213-[4-[(2R)-2-Aminopropoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine

Step 13-Bromo-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine

The title compound (0.59 g) was obtained by the same procedures as instep 1 of Example 1 using (1R)-1-(3-fluorophenyl)ethanamine (0.39 g)instead of phenylmethanamine.

¹H-NMR (CDCl₃) δ: 1.61 (3H, d, J=6.9 Hz), 4.83 (1H, d, J=6.3 Hz),5.01-5.06 (1H, m), 6.42 (1H, d, J=9.7 Hz), 6.93-6.97 (1H, m), 7.17 (1H,dt, J=9.9, 2.1 Hz), 7.24 (1H, d, J=7.4 Hz), 7.30 (1H, td, J=7.9, 5.9Hz), 7.46 (1H, s), 7.57 (1H, t, J=4.6 Hz).

Step 2 tert-ButylN-[(1R)-2-[4-[6-[[(1R)-1-(3-fluorophenyl)ethyl]amino]imidazo[1,2-b]pyridazin-3-yl]phenoxy]-1-methylethyl]carbamate

1,4-Dioxane (25 ml) and water (5 ml) were added to the compound (0.34 g)obtained in the preceding step 1, the compound (0.39 g) obtained inReference Example 15, potassium carbonate (0.55 g), and a[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethaneadduct (81 mg), and the mixture was heated to reflux for 1.5 hours undera nitrogen atmosphere. After cooling, water was added to the reactionsolution, followed by extraction with ethyl acetate. The extract waswashed with saturated saline and then dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure. Theobtained residue was purified by silica gel column chromatography (ethylacetate-methanol) to obtain the title compound (0.39 g).

¹H-NMR (CDCl₃) δ: 1.33 (3H, d, J=6.7 Hz), 1.48 (9H, s), 1.57 (3H, d,J=6.7 Hz), 3.99 (2H, d, J=3.6 Hz), 4.10-4.13 (1H, m), 4.68 (1H, d, J=4.8Hz), 4.83 (1H, br s), 4.92 (1H, dq, J=4.8, 6.7 Hz), 6.47 (1H, d, J=9.7Hz), 6.90 (2H, d, J=9.1 Hz), 6.97 (1H, td, J=8.5, 2.4 Hz), 7.11-7.14(1H, m), 7.20 (1H, d, J=7.9 Hz), 7.36 (1H, td, J=7.9, 6.0 Hz), 7.61-7.62(2H, m), 7.67 (2H, d, J=9.7 Hz).

Step 33-[4-[(2R)-2-Aminopropoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine

To a solution of the compound (0.39 g) obtained in the preceding step 1in methanol (3 ml), a solution of 4 N hydrochloric acid in 1,4-dioxane(8 ml) was added, and the mixture was stirred at room temperature for 40minutes. The reaction solution was concentrated under reduced pressure.A 1 N aqueous sodium hydroxide solution was added to the obtainedresidue, followed by extraction with chloroform-methanol. The extractwas washed with saturated saline and then dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure. Theobtained residue was purified by silica gel column chromatography (basicsilica gel, chloroform-methanol) to obtain the title compound (0.09 g).

¹H-NMR (CDCl₃) δ: 1.21 (3H, d, J=6.7 Hz), 1.57 (3H, d, J=6.7 Hz),3.37-3.41 (1H, m), 3.75 (1H, dd, J=9.1, 7.9 Hz), 3.93 (1H, dd, J=9.1,4.2 Hz), 4.67 (1H, d, J 4.8 Hz), 4.92 (1H, dq, J=4.8, 6.7 Hz), 6.47 (1H,d, J 9.7 Hz), 6.89-6.92 (2H, m), 6.97 (1H, td, J=8.5, 3.2 Hz), 7.11-7.14(1H, m), 7.20 (1H, d, J=7.3 Hz), 7.30-7.37 (1H, m), 7.60-7.63 (2H, m),7.67 (2H, d, J=8.5 Hz).

¹H-NMR (DMSO-d₆) δ: 1.08 (3H, d, J=6.0 Hz), 1.48 (3H, d, J=7.3 Hz), 1.65(2H, br s), 3.12-3.21 (1H, m), 4.19-4.19 (2H, m), 4.80-4.89 (1H, m),6.77 (1H, d, J=9.7 Hz), 6.93 (2H, d, J=9.1 Hz), 7.03 (1H, td, J=8.5, 2.2Hz), 7.22-7.29 (2H, m), 7.37-7.44 (1H, m), 7.62 (1H, d, J=6.0 Hz),7.70-7.77 (4H, m).

ESI-MS (m/z): 406 (M+H)⁺.

The following compounds were obtained by the same procedures as inExample 21 with the compound obtained in step 1 of Example 21 as thestarting material using the compounds obtained in the ReferenceExamples.

TABLE 14-1 Reference Example Example Structure and name Instrumentaldata 22 3

¹H-NMR (CDCl₃) δ: 1.57 (3H, d, J = 6.9 Hz), 1.96-2.05 (1H, m), 2.10-2.19(1H, m), 2.93-2.95 (1H, m), 3.07 (1H, dd, J = 12.6, 5.2 Hz), 3.19-3.26(2H, m), 4.74 (1H, d, J = 5.2 Hz), 4.87-4.95 (2H, m), 6.48 (1H, d, J =9.7 Hz), 6.86 (2H, d, J = 8.6 Hz), 6.97 (1H, td, J = 8.2, 2.1 Hz), 7.12(1H, d, J = 9.7 Hz), 7.20 (1H, d, J = 8.0 Hz), 7.33 (1H, td, J = 7.9,5.9 Hz), 7.59 (2H, dd, J = 9.5, 2.6 Hz), 7.65 (1H, s), 7.67 (1H, d, J =9.7 Hz). N-[(1R)-1-(3- Fluorophenyl)ethyl]-3-[4-[(3R)- pyrrolidin-3-yl]oxyphenyl]imidazo[1,2- b]pyridazin-6-amine 23 5

¹H-NMR (CDCl₃) δ: 1.56 (3H, d, J = 6.9 Hz), 1.64-1.66 (1H, m), 2.05-2.07(1H, m), 2.60-2.73 (1H, m), 2.89-2.91 (1H, m), 2.99-3.02 (1H, m),3.09-3.11 (1H, m), 3.21 (1H, dd, J = 11.2, 7.7 Hz), 3.90-4.02 (2H, m),4.75 (1H, d, J = 5.2 Hz), 4.89-4.94 (1H, m), 6.47 (1H, d, J = 9.2 Hz),6.89 (2H, d, J = 8.6 Hz), 6.96 (1H, td, J = 8.2, 2.3 Hz), 7.12 (1H, d, J= 9.7 Hz), 7.20 (1H, d, J = 8.0 Hz), 7.34 (1H, td, J = 7.9, 5.9 Hz),7.61 (2H, d, J = 8.6 Hz), 7.65 (1H, s), 7.67 (1H, d, J = 9.7 Hz).N-[(1R)-1-(3- Fluorophenyl)ethyl]-3-[4-[[(3R)- pyrrolidin-3-yl]methoxy]phenyl]imidazo[1,2- b]pyridazin-6-amine 24 1

  N-[(1R)-1-(3- Fluorophenyl)ethyl]-3-[4-[[(2S)- pyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.56 (3H, d, J = 6.6 Hz), 1.58-1.63 (1H, m), 1.78-1.86 (2H, m),1.93-2.01 (1H, m), 2.96 (1H, dt, J = 10.7, 7.1 Hz), 3.02-3.08 (1H, m),3.53-3.56 (1H, m), 3.91 (1H, dd, J = 9.2, 6.8 Hz), 3.98 (1H, dd, J =9.2, 5.1 Hz), 4.67 (1H, d, J = 5.1 Hz), 4.92 (1H, dq, J = 5.1, 6.6 Hz),6.45 (1H, d, J = 9.8 Hz), 6.88-6.91 (2H, m), 6.93-6.98 (1H, m),7.09-7.12 (1H, m), 7.19 (1H, d, J = 7.8 Hz), 7.33 (1H, td, J = 8.0, 5.9Hz), 7.58-7.61 (2H, m), 7.66 (2H, d, J = 9.0 Hz). ¹H-NMR (DMSO-d₆) δ:1.42-1.52 (1H, m), 1.48 (3H, d, J = 6.7 Hz), 1.60- 1.77 (2H, m),1.83-1.91 (1H, m), 2.77- 2.88 (2H, m), 3.36-3.44 (1H, m), 3.84 (2H, d, J= 6.0 Hz), 4.80-4.88 (1H, m), 6.76 (1H, d, J = 9.1 Hz), 6.92 (2H, d, J =8.5 Hz), 7.03 (1H, td, J = 8.6, 2.2 Hz), 7.22-7.29 (2H, m), 7.36-7.43(1H, m), 7.62 (1H, d, J = 6.0 Hz), 7.71-7.77 (4H, m). ESI-MS (m/z): 432(M + H)⁺.

TABLE 14-2 25 27

  3-[4-(Azetidin-3-yloxy)phenyl]-N- [(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.58 (3H, d, J = 7.0 Hz), 3.83-3.88 (2H, m), 3.97-4.01 (2H, m), 4.72(1H, br s), 4.89-4.93 (1H, m), 5.07 (1H, tt, J = 6.2, 6.0 Hz), 6.49 (1H,d, J = 9.8 Hz), 6.75-6.77 (2H, m), 6.98 (1H, td, J = 8.3, 2.6 Hz),7.11-7.14 (1H, m), 7.20 (1H, d, J = 7.8 Hz), 7.35 (1H, td, J = 8.0, 5.9Hz), 7.58-7.60 (2H, m), 7.66 (1H, s), 7.68 (1H, d, J = 9.8 Hz). ESI-MS(m/z): 404 (M + H)⁺. 26  7

  3-[4-(2-Aminoethoxy)phenyl]-N- [(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.53 (3H, d, J = 6.6 Hz), 3.10 (2H, t, J = 5.2 Hz), 4.02 (2H, t, J = 5.2Hz), 4.67 (1H, d, J = 6.6 Hz), 4.89 (1H, dq, J = 6.6, 6.6 Hz), 6.44 (1H,d, J = 9.8 Hz), 6.86-6.89 (2H, m), 6.91-6.95 (1H, m), 7.07-7.11 (1H, m),7.16 (1H, d, J = 7.4 Hz), 7.28-7.34 (1H, m), 7.57-7.59 (2H, m),7.63-7.65 (2H, m). ESI-MS (m/z): 392 (M + H)⁺. 27 28

  3-[4-(Azetidin-3- ylmethoxy)phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.53 (3H, d, J = 6.3 Hz), 3.14-3.17 (1H, m), 3.55 (2H, dd, J = 7.9, 6.3Hz), 3.78 (2H, t, J = 7.9 Hz), 4.15 (2H, d, J = 6.6 Hz), 4.65 (1H, brs), 4.89 (1H, dq, J = 6.3, 6.3 Hz), 6.43 (1H, d, J = 9.8 Hz), 6.88 (2H,d, J = 10.7 Hz), 6.93 (1H, td, J = 8.3, 2.2 Hz), 7.08-7.10 (1H, m), 7.17(1H, d, J = 7.8 Hz), 7.29-7.33 (1H, m), 7.58 (2H, d, J = 10.7 Hz), 7.64(2H, d, J = 8.6 Hz). ESI-MS (m/z): 418 (M + H)⁺. 28  9

  3-[4-(3-Aminopropoxy)phenyl]-N- [(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.57 (3H, d, J = 7.0 Hz), 1.98 (2H, tt, J = 6.8, 6.1 Hz), 2.96 (2H, t, J= 6.8 Hz), 4.13 (2H, t, J = 6.1 Hz), 4.69 (1H, br s), 4.90-4.96 (1H, m),6.47 (1H, d, J = 9.8 Hz), 6.90-6.93 (2H, m), 6.95-7.00 (1H, m),7.12-7.14 (1H, m), 7.20 (1H, d, J = 7.8 Hz), 7.35 (1H, td, J = 8.0, 5.9Hz), 7.60-7.63 (2H, m), 7.68 (2H, d, J = 9.4 Hz). ESI-MS (m/z): 406 (M +H)⁺.

TABLE 14-3 29 10

  N-[(1R)-1-(3-Fluorophenyl)ethyl]- 3-[4-[2-(methylamino)ethoxy]phenyl]imidazo [1,2-b]pyridazin-6-amine ¹H-NMR(CDCl₃) δ: 1.53 (3H, d, J = 7.0 Hz), 2.51 (3H, s), 2.98 (2H, t, J = 5.2Hz), 4.10 (2H, t, J = 5.2 Hz), 4.65 (1H, d, J = 5.1 Hz), 4.88 (1H, dq, J= 5.1, 7.0 Hz), 6.43 (1H, d, J = 9.4 Hz), 6.86-6.96 (3H, m), 7.07-7.10(1H, m), 7.16 (1H, d, J = 8.7 Hz), 7.31 (1H, td, J = 7.8, 5.9 Hz), 7.56-7.65 (3H, m). ESI-MS (m/z): 406 (M + H)⁺. 30 26

  3-[4-[[(2S)-Azetidin-2- yl]methoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.53 (3H, d, J = 7.0 Hz), 2.23-2.29 (1H, m), 2.37-2.45 (1H, m),3.45-3.50 (1H, m), 3.69 (1H, q, J = 8.0 Hz), 4.00-4.12 (1H, m),4.23-4.30 (1H, m), 4.67 (1H, d, J = 5.1 Hz), 4.89 (1H, dq, J = 5.1, 7.0Hz), 6.43 (1H, d, J = 9.8 Hz), 6.87-6.96 (3H, m), 7.09 (1H, dt, J = 9.8,2.1 Hz), 7.15-7.17 (1H, m), 7.28-7.33 (1H, m), 7.57-7.65 (4H, m). ESI-MS(m/z): 418 (M + H)⁺. 31 11

  N-[(1R)-3-(3-Fluorophenyl)ethyl]- 3-[4-[3-(methylamino)propoxy]phenyl] imidazo[1,2-b]pyridazine-6-amine ¹H-NMR(CDCl₃) δ: 1.53 (3H, d, J = 7.0 Hz), 1.98 (2H, tt, J = 6.8, 6.3 Hz),2.45 (3H, s), 2.78 (2H, t, J = 6.8 Hz), 4.07 (2H, t, J = 6.3 Hz), 4.65(1H, d, J = 5.5 Hz), 4.89 (1H, dq, J = 5.5, 7.0 Hz), 6.43 (1H, d, J =9.8 Hz), 6.85-6.88 (2H, m), 6.91-6.95 (1H, m), 7.07-7.10 (1H, m), 7.16(1H, d, J = 7.9 Hz), 7.31 (1H, td, J = 7.9, 6.0 Hz), 7.56-7.59 (2H, m),7.63 (2H, d, J = 9.4 Hz). ESI-MS (m/z): 420 (M + H)⁺. 32 34

  3-[4-(cis-2- Aminocyclopentoxy)phenyl]-N- [(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.58 (3H, d, J = 7.0 Hz), 1.66-2.06 (6H, m), 3.39-3.43 (1H, m),4.51-4.55 (1H, m), 4.70 (1H, d, J = 5.1 Hz), 4.93 (1H, dq, J = 5.1, 7.0Hz), 6.48 (1H, d, J = 9.4 Hz), 6.91-6.93 (2H, m), 6.96-7.00 (1H, m),7.12-7.15 (1H, m), 7.21 (1H, d, J = 7.8 Hz), 7.32-7.38 (1H, m),7.59-7.63 (2H, m), 7.67 (1H, s), 7.68 (1H, d, J = 9.8 Hz). ESI-MS (m/z):432 (M + H)⁺.

TABLE 14-4 33 36

  N-[(1R)-1-(3-Fluorophenyl)ethyl]- 3-[4-[[(2S,4S)-4-fluoropyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.57 (3H, d, J = 7.0 Hz), 1.95-2.08 (1H, m), 2.21-2.37 (1H, m), 3.01(1H, ddd, J = 25.6, 12.9, 3.9 Hz), 3.36-3.44 (1H, m), 3.57-3.61 (1H, m),4.04-4.15 (2H, m), 4.69 (1H, d, J = 5.5 Hz), 4.92 (1H, dq, J = 5.5, 7.0Hz), 5.27 (1H, dt, J = 54.7, 4.7 Hz), 6.47 (1H, d, J = 9.4 Hz),6.91-6.99 (3H, m), 7.12 (1H, dt, J = 9.9, 2.1 Hz), 7.19-7.21 (1H, m),7.35 (1H, td, J = 7.9, 6.0 Hz), 7.60-7.63 (2H, m), 7.67 (2H, d, J = 9.4Hz). ESI-MS (m/z): 450 (M + H)⁺. 34 35

  3-[4-(trans-2- Aminocyclopentoxy)phenyl]-N- [(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.43-1.48 (1H, m), 1.57 (3H, d, J = 6.7 Hz), 1.78-1.87 (3H, m),2.05-2.15 (1H, m), 2.20-2.25 (1H, m), 3.47-3.53 (1H, m), 4.35-4.38 (1H,m), 4.69 (1H, d, J = 5.1 Hz), 4.92 (1H, dq, J = 5.1, 6.7 Hz), 6.47 (1H,d, J = 9.4 Hz), 6.89 (2H, d, J = 7.8 Hz), 6.97 (1H, td, J = 8.4, 2.3Hz), 7.12-7.14 (1H, m), 7.20 (1H, d, J = 7.8 Hz), 7.34 (1H, td, J = 7.8,5.9 Hz), 7.57-7.61 (2H, m), 7.66 (1H, s), 7.67 (1H, d, J = 9.8 Hz).ESI-MS (m/z): 432 (M + H)⁺. 35 12

  3-[4-(2-Aminopropoxy)phenyl]-N- [(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.21 (3H, d, J = 6.7 Hz), 1.57 (3H, d, J = 6.7 Hz), 3.36-3.41 (1H, m),3.72-3.77 (1H, m), 3.92-3.96 (1H, m), 4.67-4.70 (1H, br m), 4.89-4.96(1H, m), 6.46 (1H, d, J = 9.7 Hz), 6.91 (2H, d, J = 8.5 Hz), 6.97 (1H,td, J = 8.5, 2.4 Hz), 7.12 (1H, d, J = 9.7 Hz), 7.20 (1H, d, J = 7.9Hz), 7.30-7.37 (1H, m), 7.62 (2H, d, J = 8.5 Hz), 7.66 (1H, s), 7.67(1H, d, J = 9.5 Hz). ESI-MS (m/z): 406 (M + H)⁺. 36 13

  3-[4-[(1R,2S)-2- Aminocyclopentoxy]phenyl]-N- [(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.57 (3H, d, J = 6.7 Hz), 1.63-1.73 (2H, m), 1.81-2.08 (4H, m),3.39-3.44 (1H, m), 4.51-4.54 (1H, m), 4.73-4.75 (1H, br m), 4.89-4.96(1H, m), 6.47 (1H, d, J = 9.7 Hz), 6.89-6.93 (2H, m), 6.97 (1H, td, J =8.5, 2.4 Hz), 7.11- 7.14 (1H, m), 7.20 (1H, d, J = 7.9 Hz), 7.30-7.37(1H, m), 7.59-7.63 (2H, m), 7.66 (1H, s), 7.67 (1H, d, J = 9.7 Hz).ESI-MS (m/z): 432 (M + H)⁺.

TABLE 14-5 37 37

  3-[4-[2- (Cyclopropylamino)ethoxy]phenyl]- N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:0.39-0.43 (2H, m), 0.45-0.52 (2H, m), 1.57 (3H, d, J = 6.7 Hz),2.22-2.27 (1H, m), 3.14 (2H, t, J = 5.1 Hz), 4.14 (2H, t, J = 5.1 Hz),4.70 (1H, d, J = 5.4 Hz), 4.92 (1H, dq, J = 5.4, 6.7 Hz), 6.47 (1H, d, J= 9.1 Hz), 6.90-6.92 (2H, m), 6.95-6.99 (1H, m), 7.20 (1H, d, J = 7.9Hz), 7.34 (1H, td, J = 7.9, 6.0 Hz), 7.60- 7.62 (2H, m), 7.67 (2H, d, J= 9.1 Hz). ESI-MS (m/z): 432 (M + H)⁺. 38 38

  N-[(1R)-1-(3-Fluorophenyl)ethyl]- 3-[4-[2-(methylamino)propoxy]phenyl] imidazo[1,2-b]pyridazin-6-amine ¹H-NMR(CDCl₃) δ: 1.19 (3H, d, J = 6.7 Hz), 1.57 (3H, d, J = 6.7 Hz), 2.52 (3H,s), 3.02-3.08 (1H, m), 3.86-3.91 (1H, m), 3.93-3.98 (1H, m), 4.70 (1H,d, J = 4.8 Hz), 4.92 (1H, dq, J = 4.8, 6.7 Hz), 6.47 (1H, d, J = 9.7Hz), 6.89-6.92 (2H, m), 6.97 (1H, td, J = 8.2, 2.4 Hz), 7.11-7.14 (1H,m), 7.20 (1H, d, J = 7.3 Hz), 7.34 (1H, td, J = 7.9, 6.0 Hz), 7.60-7.63(2H, m), 7.66 (1H, s), 7.67 (1H, d, J = 9.1 Hz). ESI-MS (m/z): 420 (M +H)⁺. 39 39

  3-[4-[(1- Aminocyclopropyl)methoxy]phenyl]- N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:0.68 (2H, dd, J = 6.3, 5.1 Hz), 0.79 (2H, dd, J = 6.3, 4.5 Hz), 1.57(4H, d, J = 6.7 Hz), 3.90 (2H, s), 4.67 (1H, d, J = 5.4 Hz), 4.92 (1H,dq, J = 5.4, 6.7 Hz), 6.47 (1H, d, J = 9.7 Hz), 6.90- 6.92 (2H, m), 6.97(1H, td, J = 8.5, 2.2 Hz), 7.11-7.14 (1H, m), 7.20 (1H, d, J = 7.9 Hz),7.35 (1H, td, J = 7.9, 6.0 Hz), 7.60-7.63 (2H, m), 7.66 (1H, s), 7.68(1H, d, J = 9.1 Hz). ESI-MS (m/z): 418 (M + H)⁺. 40 14

  3-[4-[(1S,2R)-2- Aminocyclopentoxy]phenyl]-N- [(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.57 (3H, d, J = 7.0 Hz), 1.62-1.73 (2H, m), 1.81-2.10 (4H, m),3.38-3.43 (1H, m), 4.51-4.54 (1H, m), 4.69 (1H, br s), 4.89-4.96 (1H,m), 6.47 (1H, d, J = 9.7 Hz), 6.90-6.92 (2H, m), 6.97 (1H, td, J = 8.3,2.6 Hz), 7.11-7.15 (1H, m), 7.20 (1H, d, J = 7.9 Hz), 7.34 (1H, td, J =7.9, 6.0 Hz), 7.59-7.61 (2H, m), 7.67 (2H, d, J = 9.1 Hz). ESI-MS (m/z):432 (M + H)⁺.

TABLE 14-6 41 16

  3-[4-[(2S)-2- Aminopropoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.21 (3H, d, J = 6.7 Hz), 1.57 (3H, d, J = 6.7 Hz), 3.35-3.43 (1H, m),3.74 (1H, dd, J = 9.1, 7.9 Hz), 3.94 (1H, dd, J = 9.1, 4.2 Hz), 4.70(1H, br s), 4.89-4.96 (1H, m), 6.47 (1H, d, J = 9.4 Hz), 6.89-6.92 (2H,m), 6.93-6.99 (1H, m), 7.12 (1H, dt, J = 9.9, 2.0 Hz), 7.20 (1H, d, J =7.9 Hz), 7.30-7.37 (1H, m), 7.60-7.63 (2H, m), 7.66-7.69 (2H, m). ESI-MS(m/z): 406 (M + H)⁺. 42 17

  2-[2-[4-[6-[[(1R)-1-(3- Fluorophenyl)ethyl]amino]imidazo[1,2-b]pyridazin-3-yl]phenoxy]ethyl amino]ethanol ¹H-NMR (CDCl₃) δ: 1.56(3H, d, J = 6.8 Hz), 1.73 (1H, br s), 2.90 (2H, t, J = 5.1 Hz), 3.08(2H, t, J = 4.8 Hz), 3.70 (2H, t, J = 5.1 Hz), 4.14 (2H, t, J = 4.8 Hz),4.70 (1H, d, J = 4.8 Hz), 4.92 (1H, dq, J = 4.8, 6.8 Hz), 6.47 (1H, d, J= 9.7 Hz), 6.90 (2H, d, J = 9.1 Hz), 6.94-6.99 (1H, m), 7.11-7.13 (1H,m), 7.20 (1H, d, J = 7.3 Hz), 7.30-7.37 (1H, m), 7.61 (2H, d, J = 8.5Hz), 7.67 (2H, d, J = 9.1 Hz). ESI-MS (m/z): 436 (M + H)⁺. 43 29

  3-[4-[[(2S)-Azetidin-2- yl]methoxy]-2-fluoro-phenyl]-N- [(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.56 (3H, d, J = 6.7 Hz), 2.27-2.32 (1H, m), 2.39-2.45 (1H, m),3.47-3.52 (1H, m), 3.73 (1H, q, J = 7.9 Hz), 3.99-4.08 (2H, m),4.28-4.33 (1H, m), 4.67 (1H, d, J = 5.4 Hz), 4.89 (1H, dq, J = 5.4, 6.7Hz), 6.49 (1H, d, J = 9.7 Hz), 6.67-6.76 (2H, m), 6.90-6.98 (1H, m),7.06-7.09 (1H, m), 7.15-7.17 (1H, m), 7.30-7.35 (1H, m), 7.61-7.70 (2H,m), 7.77 (1H, d, J = 3.6 Hz). ESI-MS (m/z): 436 (M + H)⁺. 44 30

  3-[4-[[(2S)-Azetidin-2- yl]methoxy]-3-fluoro-phenyl]-N- [(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.58 (3H, d, J = 7.0 Hz), 2.25-2.33 (1H, m), 2.40-2.48 (1H, m),3.48-3.53 (1H, m), 3.72 (1H, q, J = 7.9 Hz), 4.10-4.16 (2H, m),4.30-4.37 (1H, m), 4.72 (1H, d, J = 5.4 Hz), 4.97 (1H, dq, J = 5.4, 7.0Hz), 6.49 (1H, d, J = 9.1 Hz), 6.92-7.01 (2H, m), 7.11 (1H, dt, J =10.1, 2.0 Hz), 7.21-7.23 (1H, m), 7.30-7.37 (1H, m), 7.40-7.42 (1H, m),7.65-7.69 (3H, m). ESI-MS (m/z): 436 (M + H)⁺.

TABLE 14-7 45 18

  2-Amino-3-[4-[6-[[(1R)-1-(3- fluorophenyl)ethyl]amino]imidazo[1,2-b]pyridazin-3- yl]phenoxy]propan-1-ol ¹H-NMR (CDCl₃) δ: 1.57 (3H,d, J = 6.7 Hz), 3.34-3.37 (1H, m), 3.66 (1H, dd, J = 10.8, 6.0 Hz), 3.78(1H, dd, J = 10.8, 4.5 Hz), 3.96-4.00 (1H, m), 4.04-4.08 (1H, m), 4.69(1H, d, J = 5.4 Hz), 4.92 (1H, dq, J = 5.4, 6.7 Hz), 6.47 (1H, d, J =9.7 Hz), 6.88-6.93 (2H, m), 6.97 (1H, td, J = 8.3, 2.6 Hz), 7.10-7.14(1H, m), 7.20 (1H, t, J = 7.3 Hz), 7.30-7.37 (1H, m), 7.60- 7.63 (2H,m), 7.67 (2H, d, J = 10.9 Hz). ESI-MS (m/z): 422 (M + H)⁺. 46 19

  N-[(1R)-1-(3-Fluorophenyl)ethyl]- 3-[6-[2-(methylamino)ethoxy]-3-pyridyl]imidazo[1,2-b]pyridazin-6- amine ¹H-NMR (CDCl₃) δ: 1.57 (3H, d,J = 6.7 Hz), 2.54 (3H, s), 3.02 (2H, t, J = 5.1 Hz), 4.48 (2H, t, J =5.1 Hz), 4.71 (1H, d, J = 5.4 Hz), 4.87-4.93 (1H, m), 6.49 (1H, d, J =9.7 Hz), 6.74 (1H, d, J = 8.5 Hz), 6.93- 7.00 (1H, m), 7.08-7.11 (1H,m), 7.17 (1H, d, J = 7.9 Hz), 7.33 (1H, td, J = 8.0, 5.6 Hz), 7.67-7.70(2H, m), 7.77 (1H, dd, J = 9.1, 2.4 Hz), 8.54 (1H, d, J = 2.4 Hz). 47 40

  N-[(1R)-1-(3-Fluorophenyl)ethyl]- 3-[6-[[(2S,4S)-4-fluoropyrrolidin-2-yl]methoxy]-3- pyridyl]imidazo[1,2-b]pyridazin-6- amine ¹H-NMR (CDCl₃)δ: 1.57 (3H, d, J = 7.0 Hz), 1.88-2.03 (1H, m), 2.20-2.35 (1H, m), 2.97(1H, ddd, J = 35.1, 13.3, 3.9 Hz), 3.40 (1H, dd, J = 20.9, 13.3 Hz),3.56-3.62 (1H, m), 4.43 (1H, dd, J = 10.9, 6.7 Hz), 4.50 (1H, dd, J =10.9, 4.8 Hz), 4.70 (1H, d, J = 5.4 Hz), 4.87-4.93 (1H, m), 5.25 (1H,dt, J = 54.6, 4.7 Hz), 6.49 (1H, d, J = 9.7 Hz), 6.76 (1H, d, J = 8.5Hz), 6.95 (1H, td, J = 8.5, 1.8 Hz), 7.09 (1H, dt, J = 10.1, 2.0 Hz),7.17 (1H, d, J = 7.9 Hz), 7.33 (1H, td, J = 7.9, 6.0 Hz), 7.67 (1H, s),7.68 (1H, d, J = 10.9 Hz), 7.79 (1H, dd, J = 8.5, 2.4 Hz), 8.53 (1H, d,J = 2.4 Hz). ESI-MS (m/z): 451 (M + H)⁺. 48 20

  5-[6-[[(1R)-1-(3- Fluorophenyl)ethyl]amino]imidazo[1,2-b]pyridazin-3-yl]-2-[[(2S)- pyrrolidin-2- yl]methoxy]benzonitrile¹H-NMR (CDCl₃) δ: 1.60 (3H, d, J = 6.7 Hz), 1.61-1.70 (1H, m), 1.77-2.06(3H, m), 2.96-3.03 (1H, m), 3.06-3.12 (1H, m), 3.60-3.64 (1H, m), 4.03(1H, dd, J = 9.1, 6.7 Hz), 4.10 (1H, dd, J = 9.1, 5.1 Hz), 4.78 (1H, d,J = 5.4 Hz), 4.92-4.99 (1H, m), 6.52 (2H, d, J = 9.7 Hz), 6.95 (1H, d, J= 9.1 Hz), 7.09 (1H, dt, J = 9.9, 2.0 Hz), 7.24-7.26 (1H, m ), 7.37 (1H,td, J = 7.9, 6.0 Hz), 7.69 (2H, d, J = 98.1 Hz), 7.80 (1H, dd, J = 8.8,2.1 Hz), 8.19 (1H, d, J = 1.8 Hz). ESI-MS (m/z): 457 (M + H)⁺.

TABLE 14-8 49 21

  3-[4-[(2S)-2- Aminobutoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.05 (3H, t, J = 7.6 Hz), 1.42-1.70 (2H, m), 1.57 (3H, d, J = 6.7 Hz),3.12-3.16 (1H, m), 3.79 (1H, dd, J = 9.1, 7.6 Hz), 4.01 (1H, dd, J =9.1, 3.6 Hz), 4.71 (1H, d, J = 4.8 Hz), 4.89-4.96 (1H, m), 6.47 (1H, d,J = 9.7 Hz), 6.91 (2H, d, J = 9.1 Hz), 6.97 (1H, td, J = 8.5, 1.8 Hz),7.12 (1H, dt, J = 9.9, 2.0 Hz), 7.20 (1H, d, J = 7.9 Hz), 7.34 (1H, td,J = 7.9, 6.0 Hz), 7.62 (2H, d, J = 9.1 Hz), 7.66 (1H, s), 7.67 (21H, d,J = 9.6 Hz). ESI-MS (m/z): 420 (M + H)⁺. 50  2

  N-[(1R)-1-(3-Fluorophenyl)ethyl]- 3-[3-[[(2S)-pyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.59 (3H, d, J = 6.7 Hz), 1.73-2.01 (4H, m), 2.92-3.06 (2H, m),3.52-3.59 (1H, m), 3.92 (1H, dd, J = 9.1, 6.7 Hz), 3.97 (1H, dd, J =9.1, 5.4 Hz), 4.70 (1H, d, J = 6.0 Hz), 4.98-5.04 (1H, m), 6.47 (1H, d,J = 9.1 Hz), 6.87 (1H, dd, J = 7.6, 2.1 Hz), 6.94 (1H, td, J = 8.5, 2.0Hz), 7.13 (1H, dt, J = 9.9, 2.1 Hz), 7.21 (1H, d, J = 7.9 Hz), 7.25-7.37(3H, m), 7.51 (1H, t, J = 2.1 Hz), 7.68 (1H, d, J = 9.7 Hz), 7.75 (1H,s). ESI-MS (m/z): 432 (M + H)⁺. 51 22

  3-[4-(4-trans- Aminocyclobutyl)phenyl]-N- [(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.57 (3H, d, J = 6.7 Hz), 2.22-2.28 (2H, m), 2.50-2.56 (2H, m),3.81-3.87 (1H, m), 4.68 (1H, d, J = 4.8 Hz), 4.89-4.94 (2H, m), 6.46(1H, d, J = 9.7 Hz), 6.79 (2H, d, J = 8.5 Hz), 6.96 (1H, td, J = 8.5,2.4 Hz), 7.12 (1H, dt, J = 9.9, 2.0 Hz), 7.19 (1H, d, J = 7.9 Hz), 7.34(1H, td, J = 7.9, 6.0 Hz), 7.59 (2H, d, J = 8.5 Hz), 7.67 (2H, d, J =10.3 Hz). ESI-MS (m/z): 418 (M + H)⁺. 52 23

  3-[4-[(2R)-2- Aminobutoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.04 (3H, t, J = 7.6 Hz), 1.45-1.67 (2H, m), 1.57 (3H, d, J = 6.7 Hz),3.11-3.17 (1H, m), 3.80 (1H, dd, J = 9.1, 7.9 Hz), 4.00 (1H, dd, J =9.1, 4.2 Hz), 4.68 (1H, d, J = 5.4 Hz), 4.89-4.96 (1H, m), 6.46 (1H, d,J = 9.1 Hz), 6.91 (2H, d, J = 8.5 Hz), 6.97 (1H, td, J = 8.5, 2.4 Hz),7.12 (1H, dt, J = 10.1, 2.1 Hz), 7.20 (1H, d, J = 7.9 Hz), 7.34 (1H, td,J = 7.9, 6.0 Hz), 7.62 (2H, d, J = 8.5 Hz), 7.66 (1H, s), 7.67 (1H, d, J= 9.6 Hz). ESI-MS (m/z): 420 (M + H)⁺.

TABLE 14-9 53 41

  3-[6-[(2R)-2-Aminopropoxy]-3- pyridyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.21 (3H, d, J = 6.7 Hz), 1.57 (3H, d, J = 6.7 Hz), 3.37-3.41 (1H, m),4.07 (1H, dd, J = 10.3, 7.9 Hz), 4.31 (1H, dd, J = 10.3, 4.2 Hz), 4.75(1H, d, J = 5.4 Hz), 4.87-4.94 (1H, m), 6.49 (1H, d, J = 9.7 Hz), 6.75(1H, d, J = 8.5 Hz), 6.96 (1H, td, J = 8.2, 4.2 Hz), 7.10 (1H, d, J =9.7 Hz), 7.17 (1H, d, J = 7.9 Hz), 7.33 (1H, td, J = 7.9, 6.0 Hz), 7.68(2H, d, J = 9.7 Hz), 7.79 (1H, dd, J = 8.5, 2.4 Hz), 8.54 (1H, d, J =2.4 Hz). ESI-MS (m/z): 407 (M + H)⁺. 54 43

  (2R,3R)-3-Amino-4-[4-[6-[[(1R)-1- (3-fluorophenyl)ethyl]amino]imidazo[1,2-b]pyridazin-3- yl]phenoxy]butan-2-ol ¹H-NMR (CDCl₃) δ: 1.29 (3H, d,J = 6.0 Hz), 1.57 (3H, d, J = 6.7 Hz), 3.00-3.02 (1H, m), 3.10 (1H, brs), 3.79-3.85 (1H, m), 3.96 (1H, dd, J = 9.7, 6.7 Hz), 4.11 (1H, dd, J =9.7, 4.2 Hz), 4.67 (1H, d, J = 4.8 Hz), 4.89-4.95 (1H, m), 6.47 (1H, d,J = 9.7 Hz), 6.90 (2H, d, J = 8.5 Hz), 6.97 (1H, td, J = 8.3, 2.8 Hz),7.12 (1H, dt, J = 9.9, 2.0 Hz), 7.20 (1H, d, J = 7.9 Hz), 7.34 (1H, td,J = 7.9, 6.0 Hz), 7.62 (2H, d, J = 9.1 Hz), 7.67 (2H, d, J = 9.1 Hz).ESI-MS (m/z): 436 (M + H)⁺. 55 44

  (2S,3S)-3-Amino-4-[4-[6-[[(1R)-1- (3-fluorophenyl)ethyl]amino]imidazo[1,2-b]pyridazin-3- yl]phenoxy]butan-2-ol ¹H-NMR (CDCl₃) δ: 1.29 (3H, d,J = 6.0 Hz), 1.57 (3H, d, J = 7.0 Hz), 3.00-3.02 (1H, m), 3.10 (1H, brs), 3.79-3.85 (1H, m), 3.97 (1H, dd, J = 9.1, 6.7 Hz), 4.10 (1H, dd, J =9.1, 4.2 Hz), 4.68 (1H, br s), 4.89-4.95 (1H, m), 6.47 (1H, d, J = 9.7Hz), 6.90 (2H, d, J = 8.5 Hz), 6.97 (1H, td, J = 8.5, 2.4 Hz), 7.12 (1H,dt, J = 9.7, 1.8 Hz), 7.20 (1H, d, J = 7.9 Hz), 7.34 (1H, td, J = 7.9,5.8 Hz), 7.63 (2H, d, J = 8.5 Hz), 7.66 (1H, s), 7.67 (1H, d, J = 9.7Hz). ESI-MS (m/z): 436 (M + H)⁺. 56 45

  (2S)-2-Amino-3-[4-[6-[[(1R)-1-(3- fluorophenyl)ethyl]amino]imidazo[1,2-b]pyridazin-3- yl]phenoxy]propan-1-ol ¹H-NMR (CDCl₃) δ: 1.57 (3H,d, J = 7.0 Hz), 3.34-3.37 (1H, m), 3.66 (1H, dd, J = 10.9, 6.0 Hz), 3.78(1H, dd, J = 10.9, 4.2 Hz), 3.98 (1H, dd, J = 9.1, 6.7 Hz), 4.07 (1H,dd, J = 9.1, 4.8 Hz), 4.67 (1H, d, J = 5.4 Hz), 4.89-4.95 (1H, m), 6.47(1H, d, J = 9.7 Hz), 6.90 (2H, d, J = 9.1 Hz), 6.97 (1H, td, J = 8.3,2.6 Hz), 7.12 (1H, dt, J = 10.1, 2.1 Hz), 7.20 (1H, d, J = 7.9 Hz), 7.34(1H, td, J = 7.9, 6.0 Hz), 7.62 (2H, d, J = 9.1 Hz), 7.67 (2H, d, J =10.3 Hz). ESI-MS (m/z): 422 (M + H)⁺.

TABLE 14-10 57 31

  3-[3-[[(2S)-Azetidin-2- yl]methoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.58 (3H, d, J = 6.7 Hz), 2.21-2.30 (1H, m), 2.39-2.46 (1H, m), 3.49(1H, td, J = 7.9, 4.8 Hz), 3.69 (1H, q, J = 7.9 Hz), 4.02-4.10 (2H, m),4.26-4.33 (1H, m), 4.72 (1H, br s), 4.98-5.04 (1H, m), 6.47 (1H, d, J =9.7 Hz), 6.88 (1H, dd, J = 8.2, 2.7 Hz), 6.91-6.96 (1H, m), 7.11- 7.15(1H, m), 7.21 (1H, d, J = 7.9 Hz), 7.27-7.31 (2H, m), 7.36 (1H, d, J =7.9 Hz), 7.52 (1H, t, J = 2.1 Hz), 7.68 (1H, d, J = 9.7 Hz), 7.75 (1H,s). ESI-MS (m/z): 418 (M + H)⁺. 58 46

  N-[(1R)-1-(3-Fluorophenyl)ethyl]- 3-[3-[2-(methylamino)ethoxy]phenyl]imidazo [1,2-b]pyridazin-6-amine ¹H-NMR(CDCl₃) δ: 1.59 (3H, d, J = 6.7 Hz), 2.52 (3H, s), 3.01 (2H, t, J = 5.1Hz), 4.12 (2H, t, J = 5.1 Hz), 4.69 (1H, d, J = 5.4 Hz), 4.98-5.04 (1H,m), 6.47 (1H, d, J = 9.7 Hz), 6.88 (1H, dd, J = 8.8, 2.1 Hz), 6.94 (1H,td, J = 8.3, 2.6 Hz), 7.13 (1H, dt, J = 9.9, 2.0 Hz), 7.20 (1H, d, J =7.9 Hz), 7.28-7.34 (2H, m), 7.37 (1H, d, J = 7.3 Hz), 7.48 (1H, t, J =1.8 Hz), 7.68 (1H, d, J = 9.7 Hz), 7.75 (1H, s). ESI-MS (m/z): 406 (M +H)⁺. 59 52

  (2R)-2-Amino-3-[4-[6-[[(1R)-1-(3- fluorophenyl)ethyl]amino]imidazo[1,2-b]pyridazin-3- yl]phenoxy]propan-1-ol ¹H-NMR (CDCl₃) δ: 1.57 (3H,d, J = 7.0 Hz), 3.33-3.38 (1H, m), 3.66 (1H, dd, J = 10.6, 6.0 Hz), 3.78(1H, dd, J = 10.6, 4.5 Hz), 3.98 (1H, dd, J = 9.4, 3.6 Hz), 4.06 (1H,dd, J = 9.4, 5.1 Hz), 4.68 (1H, br s), 4.84-4.95 (1H, m), 6.47 (1H, d, J= 9.1 Hz), 6.90 (2H, d, J = 8.5 Hz), 6.96 (1H, td, J = 8.2, 2.4 Hz),7.10-7.13 (1H, td, J = 7.9, 6.0 Hz), 7.62 (2H, d, J = 8.5 Hz), 7.66 (1H,s), 7.67 (1H, d, J = 8.5 Hz). ESI-MS (m/z): 422 (M + H)⁺. 60 47

  3-[3-[(2R)-2- Aminopropoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.19 (3H, d, J = 6.7 Hz), 1.59 (3H, d, J = 6.7 Hz), 3.35-3.40 (1H, m),3.74 (1H, dd, J = 8.8, 7.9 Hz), 3.93 (1H, dd, J = 8.8, 4.2 Hz), 4.72(1H, d, J = 6.0 Hz), 4.98-5.05 (1H, m), 6.47 (1H, d, J = 9.7 Hz), 6.87(1H, dd, J = 8.5, 1.8 Hz), 6.94 (1H, td, J = 8.5, 2.0 Hz), 7.13 (1H, dt,J = 9.9, 2.0 Hz), 7.21 (1H, d, J = 7.9 Hz), 7.28-7.34 (2H, m), 7.37 (1H,d, J = 7.9 Hz), 7.49 (1H, t, J = 2.1 Hz), 7.68 (1H, d, J = 9.1 Hz), 7.76(1H, s). ESI-MS (m/z): 406 (M + H)⁺.

TABLE 14-11 61 53

  3-[4-(3-cis- Aminocyclobutoxy)phenyl]-N- [(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.57 (3H, d, J = 6.7 Hz), 1.88-1.95 (2H, m), 2.93-2.98 (2H, m),3.19-3.26 (1H, m), 4.33-4.40 (1H, m), 4.67 (1H, d, J = 4.8 Hz),4.88-4.95 (1H, m), 6.47 (1H, d, J = 9.7 Hz), 6.81 (2H, d, J = 8.5 Hz),6.97 (1H, td, J = 8.5, 2.6 Hz), 7.12 (1H, dt, J = 9.9, 2.0 Hz), 7.19(1H, d, J = 7.9 Hz), 7.34 (1H, td, J = 7.9, 6.0 Hz), 7.58 (2H, d, J =8.5 Hz), 7.65 (1H, s), 7.67 (1H, d, J = 9.7 Hz). ESI-MS (m/z): 418 (M +H)⁺. 62 32

  3-[3-[[(2S)-Azetidin-2- yl]methoxy]-5-fluoro-phenyl]-N- [(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.60 (3H, d, J = 6.7 Hz), 2.22-2.29 (1H, m), 2.38-2.46 (1H, m),3.45-3.51 (1H, m), 3.71 (1H, q, J = 7.9 Hz), 4.01 (1H, dd, J = 9.1, 4.8Hz), 4.06 (1H, dd, J = 9.1, 6.3 Hz), 4.27-4.31 (1H, m), 4.77 (1H, br s),5.00-5.07 (1H, m), 6.50 (1H, d, J = 9.7 Hz), 6.59 (1H, dt, J = 10.3, 2.4Hz), 6.92 (1H, td, J = 8.0, 2.2 Hz), 7.12 (1H, dt, J = 10.1, 2.0 Hz),7.22- 7.37 (4H, m), 7.68 (1H, d, J = 9.7 Hz), 7.77 (1H, s). ESI-MS(m/z): 436 (M + H)⁺. 63 42

  3-[6-[(2S)-2-Aminopropoxy]-3- pyridyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.21 (3H, d, J = 6.0 Hz), 1.57 (3H, d, J = 6.7 Hz), 3.34-3.42 (1H, m),4.08 (1H, dd, J = 10.3, 7.9 Hz), 4.31 (1H, dd, J = 10.3, 4.2 Hz), 4.72(1H, d, J = 5.4 Hz), 4.87-4.94 (1H, m), 6.49 (1H, d, J = 9.7 Hz), 6.75(1H, d, J = 8.5 Hz), 6.93-6.98 (1H, m), 7.08-7.11 (1H, m), 7.17 (1H, d,J = 7.9 Hz), 7.30-7.36 (1H, m), 7.69 (2H, d, J = 10.9 Hz), 7.79 (1H, dd,J = 8.5, 2.4 Hz), 8.54 (1H, d, J = 2.4 Hz). ESI-MS (m/z): 407 (M + H)⁺.64 33

  3-[3-[[(2S)-Azetidin-2- yl]methoxy]-4-fluoro-phenyl]-N- [(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.59 (3H, d, J = 7.3 Hz), 2.20-2.28 (1H, m), 2.36-2.44 (1H, m),3.43-3.50 (1H, m), 3.69 (1H, q, J = 7.9 Hz), 4.10 (2H, ddd, J = 17.8,9.7, 5.7 Hz), 4.27-4.33 (1H, m), 4.72 (1H, d, J = 5.4 Hz), 4.95-5.02(1H, m), 6.49 (1H, d, J = 9.7 Hz), 6.96 (1H, td, J = 8.3, 2.6 Hz), 7.05(1H, dd, J = 10.9, 8.5 Hz), 7.10-7.12 (1H, m), 7.18 (1H, d, J = 7.9 Hz),7.27-7.35 (2H, m), 7.49 (1H, dd, J = 8.2, 2.1 Hz), 7.69 (1H, d, J = 9.7Hz), 7.69 (1H, s). ESI-MS (m/z): 436 (M + H)⁺.

TABLE 14-12 65 24

  3-[3-[(2S)-2- Aminopropoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.19 (3H, d, J = 6.7 Hz), 1.59 (3H, d, J = 7.3 Hz), 3.36-3.40 (1H, m),3.74 (1H, dd, J = 8.8, 7.9 Hz), 3.93 (1H, dd, J = 8.8, 4.2 Hz), 4.73(1H, d, J = 6.0 Hz), 4.98-5.05 (1H, m), 6.47 (1H, d, J = 9.7 Hz),6.86-6.88 (1H, m), 6.92- 6.96 (1H, m), 7.13 (1H, dt, J = 9.9, 2.0 Hz),7.21 (1H, d, J = 7.9 Hz), 7.28-7.33 (2H, m), 7.36-7.38 (1H, m),7.50-7.51 (1H, m), 7.68 (1H, d, J = 9.1 Hz), 7.76 (1H, s). ESI-MS (m/z):406 (M + H)⁺. 66 48

  N-[(1R)-1-(3-Fluorophenyl)ethyl]- 3-[3-[3-(methylamino)propoxy]phenyl] imidazo[1,2-b]pyridazin-6-amine ¹H-NMR(CDCl₃) δ: 1.59 (3H, d, J = 7.3 Hz), 2.01 (2H, tt, J = 7.0, 6.3 Hz),2.46 (3H, s), 2.79 (2H, t, J = 7.0 Hz), 4.09 (2H, t, J =6.3 Hz), 4.71(1H, d, J = 5.4 Hz), 4.98-5.05 (1H, m), 6.47 (1H, d, J = 9.7 Hz),6.85-6.88 (1H, m), 6.94 (1H, td, J = 8.5, 2.0 Hz), 7.12-7.14 (1H, m),7.21 (1H, d, J = 7.9 Hz), 7.28-7.36 (3H, m), 7.50 (1H, t, J = 1.8 Hz),7.68 (1H, d, J = 9.7 Hz), 7.75 (1H, s). ESI-MS (m/z): 420 (M + H)⁺. 6749

  3-[3-(2-Aminoethoxy)phenyl]-N- [(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.59 (3H, d, J = 6.7 Hz), 3.12 (2H, t, J = 5.1 Hz), 4.04 (2H, t, J = 5.1Hz), 4.73 (1H, br s), 4.98-5.04 (1H, m), 6.48 (1H, d, J = 9.7 Hz), 6.88(1H, d, J = 7.9, 2.4 Hz), 6.94 (1H, td, J = 8.3, 2.6 Hz), 7.12-7.14 (1H,m), 7.21 (1H, d, J = 7.9 Hz), 7.29-7.37 (3H, m), 7.49 (1H, t, J = 1.8Hz), 7.68 (1H, d, J = 9.7 Hz), 7.75 (1H, s). ESI-MS (m/z): 392 (M + H)⁺.68 50

  3-[3-(3-Aminopropoxy)phenyl]-N- [(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2- b]pyridazin-6-amine ¹H-NMR (CDCl₃) δ:1.58 (3H, d, J = 6.7 Hz), 1.93-2.00 (2H, m), 2.94 (2H, t, J = 6.7 Hz),4.10 (2H, t, J = 6.0 Hz), 4.75 (1H, br s), 4.98-5.04 (1H, m), 6.47 (1H,d, J = 9.7 Hz), 6.86-6.87 (1H, m), 6.92-6.96 (1H, m), 7.13 (1H, dt, J =9.9, 2.1 Hz), 7.21 (1H, d, J = 7.9 Hz), 7.28-7.36 (3H, m), 7.49 (1H, t,J = 2.1 Hz), 7.68 (1H, d, J = 9.7 Hz), 7.75 (1H, s). ESI-MS (m/z): 406(M + H)⁺.

Example 693-[4-(2-Dimethylaminoethoxy)phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine

Step 13-[4-(2-Dimethylaminoethoxy)phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine

The title compound (0.24 g) was obtained by the same procedures as instep 1 of Example 8 using the compound (0.28 g) obtained in Example 29.

¹H-NMR (CDCl₃) δ: 1.56 (3H, d, J=7.0 Hz), 2.37 (6H, s), 2.77 (2H, t,J=5.9 Hz), 4.13 (2H, t, J=5.9 Hz), 4.70 (1H, d, J=5.1 Hz), 4.92 (1H, dq,J=5.1, 7.0 Hz), 6.47 (1H, d, J=9.4 Hz), 6.91-6.98 (3H, m), 7.12 (1H, dt,J=9.5, 2.1 Hz), 7.19 (1H, d, J=7.4 Hz), 7.34 (1H, td, J=8.0, 5.9 Hz),7.61 (2H, dt, J=9.5, 2.5 Hz), 7.66-7.68 (2H, m).

ESI-MS (m/z): 420 (M+H)⁺.

Example 703-[4-[3-(Dimethylamino)propoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine

Step 13-[4-[3-(Dimethylamino)propoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine

The title compound (0.26 g) was obtained by the same procedures as instep 1 of Example 8 using the compound (0.28 g) obtained in Example 31.

¹H-NMR (CDCl₃) δ: 1.57 (3H, d, J=6.7 Hz), 1.98-2.02 (2H, m), 2.29 (6H,s), 2.49 (2H, t, J=7.2 Hz), 4.08 (2H, t, J=6.3 Hz), 4.67 (1H, d, J=5.1Hz), 4.90-4.96 (1H, m), 6.46 (1H, d, J=9.8 Hz), 6.90 (2H, d, J=9.0 Hz),6.94-6.99 (1H, m), 7.12 (1H, dt, J=9.9, 2.1 Hz), 7.20 (1H, d, J=7.8 Hz),7.34 (1H, td, J=8.0, 5.9 Hz), 7.62 (2H, d, J=9.0 Hz), 7.67 (2H, d, J=9.0Hz).

ESI-MS (m/z): 434 (M+H)⁺.

Example 713-[6-(2-Dimethylaminoethoxy)-3-pyridyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine

Step 13-[6-(2-Dimethylaminoethoxy)-3-pyridyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine

The title compound (0.10 g) was obtained by the same procedures as instep 1 of Example 8 using the compound obtained in Example 46.

¹H-NMR (CDCl₃) δ: 1.57 (3H, d, J=7.0 Hz), 2.37 (6H, s), 2.76 (2H, t,J=5.7 Hz), 4.48 (2H, t, J=5.7 Hz), 4.70 (1H, d, J=4.8 Hz), 4.87-4.93(1H, m), 6.49 (1H, d, J=9.7 Hz), 6.78 (1H, d, J=9.1 Hz), 6.95 (1H, td,J=8.3, 2.6 Hz), 7.07-7.11 (1H, m), 7.17 (1H, d, J=7.3 Hz), 7.33 (1H, td,J=8.0, 5.6 Hz), 7.68 (2H, d, J=10.9 Hz), 7.77 (1H, dd, J=8.5, 2.4 Hz),8.53 (1H, d, J=2.4 Hz).

Example 724-Amino-1-[4-[6-(benzylamino)imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

Step 1 tert-ButylN-[1-[4-[6-(benzylamino)imidazo[1,2-b]pyridazin-3-yl]phenyl]-5-oxopyrrolidin-3-yl]carbamate

1,4-Dioxane (10 ml) and water (5 ml) were added to the compound (100 mg)obtained in step 1 of Example 1, the compound (160 mg) obtained in step3 of Reference Example 61, sodium carbonate (52 mg), and a[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethaneadduct (27 mg), and the mixture was heated to reflux for 40 minutesunder a nitrogen atmosphere. After cooling, water was added to thereaction solution, and the mixture was subjected to extraction withethyl acetate. The extract was washed with saturated saline and thendried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure. The obtained residue was washed with an ethylacetate-diethyl ether mixed solution to obtain the title compound (125mg).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.51 (1H, dd, J=17.2, 4.4 Hz), 3.00 (1H,dd, J=17.4, 7.8 Hz), 3.77 (1H, d, J=7.8 Hz), 4.16-4.25 (1H, m), 4.44(1H, br s), 4.59 (2H, d, J=6.0 Hz), 4.76 (1H, t, J=5.0 Hz), 4.90 (1H, brs), 6.49 (1H, d, J=9.2 Hz), 7.29-7.43 (5H, m), 7.64 (2H, d, J=8.7 Hz),7.69 (1H, d, J=9.6 Hz), 7.78 (1H, s), 8.00 (2H, d, J=8.7 Hz).

Step 24-Amino-1-[4-[6-(benzylamino)imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

To a solution of the compound (125 mg) obtained in the preceding step 1in dichloromethane (10 ml), trifluoroacetic acid (2 ml) was added, andthe mixture was stirred at room temperature for 3 hours. A saturatedaqueous solution of sodium bicarbonate was added to the reactionsolution, followed by extraction with chloroform. The extract was washedwith saturated saline and then dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure. The obtained residuewas purified by silica gel column chromatography (basic silica gel,chloroform) to obtain the title compound (20 mg).

¹H-NMR (CDCl₃) δ: 2.43 (1H, dd, J=17.0, 5.0 Hz), 2.93 (1H, dd, J=17.0,7.3 Hz), 3.59 (1H, dd, J=10.1, 4.1 Hz), 3.81-3.89 (1H, m), 4.11 (1H, dd,J=9.9, 6.6 Hz), 4.59 (2H, d, J=5.5 Hz), 4.75 (1H, s), 6.49 (1H, d, J=9.6Hz), 7.28-7.44 (5H, m), 7.66 (2H, d, J=8.7 Hz), 7.69 (1H, d, J=9.2 Hz),7.78 (1H, s), 7.99 (2H, d, J=8.7 Hz).

Example 734-Amino-1-[4-[6-[(3-fluorophenyl)methoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

Step 1 tert-ButylN-[1-[4-[6-[(3-fluorophenyl)methoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]-5-oxopyrrolidin-3-yl]carbamate

The title compound (100 mg) was obtained by the same procedures as instep 1 of Example 72 using the compound (100 mg) obtained in step 1 ofExample 11 and the compound (140 mg) obtained in step 3 of ReferenceExample 61.

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.53 (1H, dd, J=17.2, 4.6 Hz), 3.02 (1H,dd, J=17.8, 8.0 Hz), 3.80 (1H, dd, J=9.7, 2.9 Hz), 4.20-4.27 (1H, m),4.46 (1H, br s), 4.88 (1H, br s), 5.40 (2H, s), 6.81 (1H, d, J=9.7 Hz),7.05 (1H, td, J=8.3, 3.1 Hz), 7.20 (1H, d, J=9.2 Hz), 7.25 (1H, d, J=8.0Hz), 7.39 (1H, td, J=8.0, 5.7 Hz), 7.73 (2H, d, J=8.6 Hz), 7.88 (1H, s),7.89 (1H, d, J=9.2 Hz), 7.96 (2H, d, J=8.6 Hz).

Step 24-Amino-1-[4-[6-[(3-fluorophenyl)methoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

The title compound (35 mg) was obtained by the same procedures as instep 2 of Example 72 with the compound (100 mg) obtained in thepreceding step 1 as the starting material.

¹H-NMR (CDCl₃) δ: 2.44 (1H, dd, J=16.7, 3.4 Hz), 2.95 (1H, dd, J=17.0,6.9 Hz), 3.62 (1H, dd, J=9.9, 2.5 Hz), 3.84-3.92 (1H, m), 4.10-4.16 (1H,m), 5.40 (2H, s), 6.80 (1H, d, J=9.6 Hz), 7.05 (1H, t, J=8.3 Hz),7.17-7.28 (2H, m), 7.35-7.42 (1H, m), 7.74 (2H, d, J=8.7 Hz), 7.87-7.90(2H, m), 7.95 (2H, d, J=9.2 Hz).

The following compounds were obtained by the same procedures as inExample 73 with the compound obtained in step 1 of Example 11 as thestarting material using the compounds obtained in the ReferenceExamples.

TABLE 15-1 Reference Example Example Structure and name Instrumenta data74 63

  4-(Aminomethyl)-1-[4-[6-[(3- fluorophenyl)methoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin- 2-one ¹H-NMR (CDCl₃) δ: 1.63 (2H, brs), 2.42-2.52 (1H, m), 2.78-2.90 (2H, m), 3.23-3.39 (2H, m), 3.73-3.79(1H, m), 4.06-4.13 (2H, m), 3.40 (2H, s), 6.79 (1H, d, J = 10.1 Hz),7.05 (1H, t, J = 8.3 Hz), 7.20 (1H, d, J = 9.2 Hz), 7.23-7.27 (1H, m),7.35-7.42 (1H, m), 7.78 (2H, d, J = 8.9 Hz), 7.86-7.89 (2H, m), 7.95(2H, d, J = 8.9 Hz). 75 64

  3-Amino-1-[4-[6-[(3- fluorophenyl)methoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin- 2-one ¹H-NMR (CDCl₃) δ: 1.65 (2H, brs), 1.86-1.98 (1H, m), 2.58-2.67 (1H, m), 3.74 (1H, dd, J = 10.1, 7.8Hz), 3.81- 3.87 (2H, m), 5.41 (2H, s), 6.81 (1H, d, J = 9.6 Hz), 7.05(1H, td, J = 8.3, 2.8 Hz), 7.20 (1H, d, J = 10.5 Hz), 7.25 (1H, d, J =7.8 Hz), 7.36-7.42 (1H, m), 7.79 (2H, d, J = 8.7 Hz), 7.88 (1H, s), 7.89(1H, d, J = 9.6 Hz), 7.97 (2H, d, J = 8.7 Hz).

TABLE 15-2 76 65

  (4S)-4-Amino-1-[4-[6-[(3- fluorophenyl)methoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin- 2-one ¹H-NMR (CDCl₃) δ: 1.55 (2H, brs), 2.41 (1H, dd, J = 16.8, 5.1 Hz), 2.91 (1H, dd, J = 16.8, 7.0 Hz),3.59 (1H, dd, J = 9.4, 4.3 Hz), 3.81-3.87 (1H, m), 4.10 (1H, dd, J =9.4, 6.6 Hz), 5.36 (2H, s), 6.76 (1H, d, J = 9.8 Hz), 7.02 (1H, td, J =8.6, 2.7 Hz), 7.16 (1H, d, J = 9.4 Hz), 7.22 (1H, d, J = 7.4 Hz), 7.35(1H, td, J = 7.8, 5.9 Hz), 7.70 (2H, d, J = 9.0 Hz), 7.84 (1H, s), 7.85(1H, d, J = 9.8 Hz), 7.92 (2H, d, J = 8.6 Hz). 77 73

  7-Amino-5-[4-[6-[(3- fluorophenyl)methoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]-7-methyl- 5-azaspiro[2.4]heptan-4-one ¹H-NMR(CDCl₃) δ: 0.87-0.98 (2H, m), 1.12-1.17 (1H, m), 1.19-1.26 (1H, m), 1.25(3H, s), 1.59 (2H, br s), 3.79 (1H, d, J = 9.7 Hz), 3.90 (1H, d, J = 9.1Hz), 5.40 (2H, s), 6.80 (1H, d, J = 9.7 Hz), 7.05 (1H, td, J = 9.1, 2.4Hz), 7.20 (1H, dt, J = 9.7, 1.8 Hz), 7.25 (1H, d, J = 7.3 Hz), 7.36-7.43 (1H, m), 7.76 (2H, d, J = 9.7 Hz), 7.88 (1H, s), 7.88 (1H, d, J =9.1 Hz), 7.95 (2H, d, J = 9.1 Hz)

Example 78(4R)-4-Amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

Step 1 tert-ButylN-[(3R)-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]-5-oxopyrrolidin-3-yl]carbamate

1,4-Dioxane was added to the compound (91 mg) obtained in step 1 ofReference Example 62, a[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethaneadduct (10 mg), bis(pinacolato)diborane (65 mg), and potassium acetate(50 mg), and the mixture was stirred at 90° C. for 1 hour under an argonatmosphere and then heated to reflux for 1 hour.

The reaction solution was temporarily brought back to room temperature.The compound (86 mg) obtained in step 1 of Example 15, a[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethaneadduct (10 mg), tripotassium phosphate (109 mg), and water (0.5 ml) wereadded thereto, and the mixture was heated to reflux for 1 hour under anargon atmosphere. Ethyl acetate and water were added to the reactionsolution to separate the aqueous and organic layers. The organic layerwas dried over anhydrous sodium sulfate and then concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (basic silica gel, n-hexane-ethylacetate→dichloromethane-methanol) to obtain the title compound (31 mg).

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 1.68 (3H, d, J=6.9 Hz), 2.55 (1H, dd,J=17.2, 4.6 Hz), 3.03 (1H, dd, J=17.2, 8.0 Hz), 3.80 (1H, dd, J=10.0,3.4 Hz), 4.24 (1H, dd, J=10.0, 6.3 Hz), 4.45-4.51 (1H, m), 5.03-5.07(1H, m), 5.93 (1H, q, J=6.9 Hz), 6.79 (1H, d, J=9.7 Hz), 6.96-7.01 (1H,m), 7.12-7.15 (1H, m), 7.21 (1H, d, J=7.4 Hz), 7.33-7.38 (1H, m),7.66-7.69 (2H, m), 7.72-7.75 (2H, m), 7.79 (1H, s), 7.85 (1H, d, J=9.7Hz).

ESI-MS (m/z): 532 (M+H)⁺.

Step 2(4R)-4-Amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

The compound (31 mg) obtained in the preceding step 1 was dissolved indichloromethane (3 ml). To the solution, a solution of 4 N hydrochloricacid in dioxane (3 ml) was added, and the mixture was stirred at roomtemperature for 1 hour. The solvent was distilled off under reducedpressure. Dichloromethane and a saturated aqueous solution of sodiumbicarbonate were added to the residue to separate the aqueous andorganic layers. The organic layer was dried over anhydrous sodiumsulfate and then concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (basic silicagel, dichloromethane-methanol) to obtain the title compound (23 mg).

¹H-NMR (CDCl₃) δ: 1.69 (3H, d, J=6.4 Hz), 2.46 (1H, dd, J=17.2, 5.2 Hz),2.96 (1H, dd, J=17.2, 7.4 Hz), 3.63 (1H, dd, J=10.0, 4.0 Hz), 3.87-3.92(1H, m), 4.15 (1H, dd, J=10.0, 6.6 Hz), 5.93 (1H, q, J=6.4 Hz), 6.79(1H, d, J=9.7 Hz), 6.99 (1H, td, J=8.4, 2.3 Hz), 7.13-7.16 (1H, m), 7.22(1H, d, J=7.4 Hz), 7.34-7.38 (1H, m), 7.69-7.75 (4H, m), 7.80 (1H, s),7.85 (1H, d, J=9.7 Hz).

ESI-MS (m/z): 432 (M+H)⁺.

Example 79(4S)-4-Amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

Step 1 tert-ButylN-[(3S)-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]-5-oxopyrrolidin-3-yl]carbamate

A mixed solvent of 1,4-dioxane (8 ml) and water (0.8 ml) was added tothe compound (501 mg) obtained in step 1 of Example 15, the compound(600 mg) obtained in step 3 of Reference Example 65, a[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethaneadduct (122 mg), and tripotassium phosphate (633 mg), and the mixturewas heated to reflux for 1.5 hours under an argon atmosphere. Then, a[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethaneadduct (122 mg) was further added thereto, and the mixture was furtherheated to reflux for 1 hour. After standing to cool, ethyl acetate andwater were added to the reaction solution to separate the aqueous andorganic layers. The organic layer was dried over anhydrous sodiumsulfate and then concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (basic silicagel, dichloromethane-methanol) to obtain the title compound (607 mg).

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 1.67 (3H, d, J=6.3 Hz), 2.58 (1H, dd,J=17.8, 4.0 Hz), 3.02 (1H, dd, J=17.8, 8.6 Hz), 3.80 (1H, dd, J=10.3,3.4 Hz), 4.20-4.25 (1H, m), 4.43-4.50 (1H, m), 5.41 (1H, d, J=6.9 Hz),5.90 (1H, q, J=6.3 Hz), 6.78 (1H, d, J=9.7 Hz), 6.97 (1H, td, J=8.0, 2.9Hz), 7.13 (1H, dt, J=9.7, 2.3 Hz), 7.20 (1H, d, J=8.0 Hz), 7.35 (1H, td,J=7.9, 5.9 Hz), 7.64-7.67 (2H, m), 7.70-7.72 (2H, m), 7.77 (1H, s), 7.84(1H, d, J=9.7 Hz).

ESI-MS (m/z): 532 (M+H)⁺.

Step 2(4S)-4-Amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

The compound (13.90 g) obtained in the preceding step 1 was dissolved indichloromethane (200 ml). To the solution, a solution of 4 Nhydrochloric acid in 1,4-dioxane (133 ml) was added under ice cooling,and the mixture was stirred at 0° C. for 2 hours. The solvent wasdistilled off under reduced pressure. Dichloromethane and a saturatedaqueous solution of sodium bicarbonate were added to the residue toseparate the aqueous and organic layers. The aqueous layer was subjectedto extraction with dichloromethane. The organic layers were combined,dried over anhydrous sodium sulfate and then concentrated under reducedpressure.

The same procedures as above were carried out using the compound (12.42g) obtained in the preceding step 1. The obtained crude products werecombined and purified by silica gel column chromatography (basic silicagel, dichloromethane-methanol; and subsequently silica gel,dichloromethane-methanol) to obtain the title compound (20.30 g).

¹H-NMR (CDCl₃) δ: 1.69 (3H, d, J=6.7 Hz), 2.46 (1H, dd, J=17.0, 4.8 Hz),2.96 (1H, dd, J=17.0, 7.6 Hz), 3.64 (1H, dd, J=9.7, 4.2 Hz), 3.86-3.92(1H, m), 4.15 (1H, dd, J=9.7, 6.0 Hz), 5.93 (1H, q, J=6.7 Hz), 6.78 (1H,d, J=9.7 Hz), 6.99 (1H, td, J=8.5, 2.4 Hz), 7.12-7.17 (1H, m), 7.22 (1H,d, J=8.0 Hz), 7.37 (1H, td, J=8.0, 5.8 Hz), 7.68-7.75 (4H, m), 7.80 (1H,s), 7.85 (1H, d, J=9.7 Hz).

¹H-NMR (DMSO-d₆) δ: 1.66 (3H, d, J=6.0 Hz), 1.93 (2H, br s), 2.25 (1H,dd, J=16.9, 4.2 Hz), 2.76 (1H, dd, J=16.6, 7.0 Hz), 3.51 (1H, dd, J=9.7,3.0 Hz), 3.65-3.71 (1H, m), 4.02 (1H, dd, J=9.7, 6.7 Hz), 6.04 (1H, q,J=6.4 Hz), 7.01 (1H, d, J=9.7 Hz), 7.10 (1H, td, J=8.5, 2.4 Hz),7.31-7.36 (2H, m), 7.39-7.45 (1H, m), 7.75 (2H, d, J=9.1 Hz), 7.90 (2H,d, J=9.1 Hz), 8.03 (1H, s), 8.09 (1H, d, J=9.7 Hz).

The following compound was obtained by the same procedures as in Example79 with the compound obtained in step 1 of Example 15 as the startingmaterial using the compound obtained in the Reference Example.

TABLE 16 Reference Example Example No. No. Structure and nameInstrumental data 80 71

  (4S)-1-[4-[6-[(1R)-1-(3- Fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]-4- (methylamino)pyrrolidin-2-one ¹H-NMR (CDCl₃)δ: 1.69 (3H, d, J = 6.6 Hz), 2.52 (3H, s), 2.54 (1H, dd, J = 17.2, 4.8Hz), 2.92 (1H, dd, J = 17.2, 7.6 Hz), 3.54-3.59 (1H, m), 3.73 (1H, dd, J= 9.76, 4.2 Hz), 4.11 (1H, dd, J = 9.7, 6.7 Hz), 5.93 (1H, q, J = 6.6Hz), 6.78 (1H, d, J = 9.7 Hz), 6.99 (1H, td, J = 8.5, 2.4 Hz), 7.13-7.17(1H, m), 7.22 (1H, d, J = 7.9 Hz), 7.33-7.39 (1H, m), 7.68-7.75 (4H, m),7.80 (1H, s), 7.85 (1H, d, J = 9.76 Hz). ESI-MS (m/z): 446 (M + H)⁺.

Example 81(4S)-4-Amino-1-[4-[6-[(3-fluorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

Step 1 tert-ButylN-[(3S)-1-[4-[6-[(3-fluorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]-5-oxopyrrolidin-3-yl]carbamate

The title compound (0.22 g) was obtained by the same procedures as instep 1 of Example 72 with the compound (0.25 g) obtained in step 1 ofExample 9 and the compound (0.36 g) obtained in step 3 of ReferenceExample 65 as starting materials.

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 2.53 (1H, dd, J=17.4, 4.5 Hz), 3.02 (1H,dd, J=17.2, 8.2 Hz), 3.25 (3H, s), 3.76-3.81 (1H, m), 4.23 (1H, dd,J=9.8, 6.7 Hz), 4.47 (1H, br s), 4.77 (2H, s), 4.89 (1H, br s), 6.78(1H, d, J=10.2 Hz), 6.97-7.03 (2H, m), 7.07 (1H, d, J=7.8 Hz), 7.31-7.37(1H, m), 7.67 (2H, d, J=9.0 Hz), 7.78 (1H, d, J=9.8 Hz), 7.85 (1H, s),8.04 (2H, d, J=9.0 Hz).

Step 2(4S)-4-Amino-1-[4-[6-[(3-fluorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

The title compound (0.15 g) was obtained by the same procedures as instep 2 of Example 72 with the compound (0.22 g) obtained in thepreceding step 1 as the starting material.

¹H-NMR (CDCl₃) δ: 2.45 (1H, dd, J=17.0, 4.9 Hz), 2.95 (1H, dd, J=16.8,7.4 Hz), 3.25 (3H, s), 3.61 (1H, dd, J=9.8, 3.9 Hz), 3.85-3.91 (1H, m),4.13 (1H, dd, J=9.8, 6.3 Hz), 4.77 (2H, s), 6.78 (1H, d, J=9.8 Hz),6.98-7.01 (2H, m), 7.08 (1H, d, J=7.4 Hz), 7.31-7.37 (1H, m), 7.68 (2H,d, J=9.0 Hz), 7.78 (1H, d, J=9.8 Hz), 7.85 (1H, s), 8.04 (2H, d, J=9.0Hz).

¹H-NMR (DMSO-d₆) δ: 1.89 (2H, br s), 2.22 (1H, dd, J=16.3, 4.2 Hz), 2.74(1H, dd, J=16.9, 7.3 Hz), 3.24 (3H, s), 3.47 (1H, dd, J=9.7, 3.6 Hz),3.62-3.68 (1H, m), 3.98 (1H, dd, J=9.7, 6.0 Hz), 4.83 (2H, s), 7.05-7.14(4H, m), 7.35-7.42 (1H, m), 7.69 (2H, d, J=9.4 Hz), 7.90 (1H, d, J=9.7Hz), 7.94 (1H, s), 8.07 (2H, d, J 9.1 Hz).

The following compounds were obtained by the same procedures as inExample 81 with the compound obtained in step 1 of Example 9 as thestarting material using the compounds obtained in the ReferenceExamples.

TABLE 17-1 Reference Example Example Structure and name Instrumentaldata 82 61

  4-Amino-1-[4-[6-[(3- fluorophenyl)methyl- methylamino]imidazo[1,2-b]pyridazin-3- yl]phenyl]pyrrolidin-2-one ¹H-NMR (CDCl₃) δ: 2.45 (1H,dd, J = 17.0, 4.9 Hz), 2.95 (1H, dd, J = 16.8, 7.4 Hz), 3.25 (3H, s),3.61 (1H, dd, J = 9.8, 3.9 Hz), 3.85-3.91 (1H, m), 4.13 (1H, dd, J =9.8, 6.3 Hz), 4.77 (2H, s), 6.78 (1H, d, J = 9.8 Hz), 6.98-7.01 (2H, m),7.08 (1H, d, J = 7.4 Hz), 7.31-7.37 (1H, m), 7.68 (2H, d, J = 9.0 Hz),7.78 (1H, d, J = 9.8 Hz), 7.85 (1H, s), 8.03 (2H, d, J = 9.0 Hz). 83 67

  (4S)-4-Amino-1-[2-fluoro-4-[6- [(3-fluorophenyl)methyl-methylamino]imidazo[1,2- b]pyridazin-3- yl]phenyl]pyrrolidin-2-one¹H-NMR (CDCl₃) δ: 2.37 (1H, dd, J = 16.9, 4.8 Hz), 2.88 (1H, dd, J =9.7, 4.2 Hz), 3.85-3.91 (1H, m), 4.06-4.15 (1H, m), 4.76 (2H, s), 6.79(1H, d, J = 9.7 Hz), 6.94-7.00 (2H, m), 7.05 (1H, d, J = 7.9 Hz),7.29-7.34 (1H, m), 7.48 (1H, t, J = 8.5 Hz), 7.77 (2H, d, J = 10.3 Hz),7.86 (1H, s), 7.95-7.99 (1H, m). 84 75

  4-Amino-1-[4-[6-[(3- fluorophenyl)methyl- methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]-4- methylpyrrolidin-2-one ¹H-NMR (CDCl₃) δ:1.46 (3H, s), 2.57 (1H, d, J = 16.9 Hz), 2.68 (1H, d, J = 16.3 Hz), 3.22(3H, s), 3.69 (1H, d, J = 9.7 Hz), 3.79 (1H, d, J = 9.7 Hz), 4.74 (2H,s), 6.75 (1H, d, J = 9.7 Hz), 7.00- 6.95 (2H, m), 7.05 (1H, d, J = 7.9Hz), 7.35-7.29 (1H, m), 7.65 (2H, d, J = 9.1 Hz), 7.75 (1H, d, J = 9.7Hz), 7.82 (1H, s), 8.01 (2H, d, J = 8.5 Hz). 85 69

  (4S)-4-Amino-1-[4-[6-[(3- fluorophenyl)methyl-methylamino]imidazo[1,2- b]pyridazin-3-yl]-3-methoxyphenyl]pyrrolidin-2-one ¹H-NMR (DMSO-d₆) δ: 1.85-1.96 (2H, br m),2.23 (1H, dd, J = 16.6, 3.9 Hz), 2.75 (1H, dd, J = 16.6, 7.3 Hz), 3.16(3H, s), 3.50 (1H, dd, J = 9.7, 3.9 Hz), 3.63-3.68 (1H, m), 3.81 (3H,s), 4.01 (1H, dd, J = 10.0, 6.3 Hz), 4.76 (2H, s), 7.04-7.13 (5H, m),7.34-7.39 (1H, m), 7.62-7.64 (1H, m), 7.80 (1H, s), 7.88 (1H, d, J = 9.7Hz), 8.00 (1H, d, J = 8.5 Hz). ESI-MS (m/z): 461 (M + H)⁺.

TABLE 17-2 86 78

  4-Amino-1-[4-[6-[(3- fluorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3- yl]phenyl]-4-methylpyrrolidin-2- one¹H-NMR (CDCl₃) δ: 1.46 (3H, s), 2.57 (1H, d, J = 16.9 Hz), 2.68 (1H, d,J = 16.9 Hz), 3.22 (3H, s), 3.69 (1H, d, J = 9.7 Hz), 3.79 (1H, d, J =9.7 Hz), 4.74 (2H, s), 6.75 (1H, d, J = 9.7 Hz), 6.95-6.99 (m, 2H),7.04-7.07 (1H, m), 7.29-7.35 (1H, m), 7.65 (2H, d, J = 9.1 Hz), 7.75(1H, d, J = 9.7 Hz), 7.83 (1H, s), 8.01 (2H, d, J = 9.1 Hz). 87 79

  4-Amino-1-[4-[6-[(3- fluorophenyl)methyl- methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]-4-methyl pyrrolidin-2-one ¹H-NMR (CDCl₃) δ:1.46 (3H, s), 2.57 (1H, d, J = 16.9 Hz), 2.68 (1H, d, J = 16.9 Hz), 3.22(3H, s), 3.69 (1H, d, J = 9.7 Hz), 3.79 (1H, d, J = 9.7 Hz), 4.74 (2H,s), 6.75 (1H, d, J = 9.7 Hz), 6.95-6.99 (2H, m), 7.04-7.07 (1H, m),7.29-7.35 (1H, m), 7.65 (2H, d, J = 9.1 Hz), 7.75 (1H, d, J = 9.7 Hz),7.83 (1H, s), 8.01 (2H, d, J = 9.1 Hz).

Example 88(4S)-4-Amino-1-[4-[6-[[(1R)-1-phenylethyl]amino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

Step 1 tert-ButylN-[(3S)-5-oxo-1-[4-[6-[[(1R)-1-phenylethyl]amino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-3-yl]carbamate

The title compound (0.42 g) was obtained by the same procedures as instep 1 of Example 72 with the compound (0.31 g) obtained in step 1 ofExample 19 as the starting material using the compound (0.47 g) obtainedin step 3 of Reference Example 65.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 1.56 (3H, d, J=6.6 Hz), 2.49 (1H, dd,J=17.4, 4.5 Hz), 2.99 (1H, dd, J=17.6, 7.8 Hz), 3.74 (1H, dd, J=10.6,3.9 Hz), 4.14-4.23 (1H, m), 4.44 (1H, br s), 4.66 (1H, d, J=5.9 Hz),4.85 (1H, br s), 4.88-4.97 (1H, m), 6.44 (1H, d, J=9.4 Hz), 7.22-7.40(5H, m), 7.57 (2H, d, J=9.4 Hz), 7.63 (1H, d, J=9.0 Hz), 7.69 (1H, s),7.75 (2H, d, J=9.0 Hz).

(4S)-4-Amino-1-[4-[6-[[(1R)-1-phenylethyl]amino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

The title compound (0.17 g) was obtained by the same procedures as instep 2 of Example 72 with the compound (0.42 g) obtained in thepreceding step 1 as the starting material.

¹H-NMR (CDCl₃) δ: 1.53 (2H, br s), 1.56 (3H, d, J=6.6 Hz), 2.41 (1H, dd,J=17.0, 4.9 Hz), 2.91 (1H, dd, J=17.0, 7.2 Hz), 3.57 (1H, dd, J=9.8, 3.9Hz), 3.81-3.86 (1H, m), 4.09 (1H, dd, J=10.2, 6.3 Hz), 4.67 (1H, d,J=5.9 Hz), 4.89-4.96 (1H, m), 6.44 (1H, d, J=9.8 Hz), 7.24-7.41 (5H, m),7.58 (2H, d, J=8.6 Hz), 7.63 (1H, d, J=9.8 Hz), 7.69 (1H, s), 7.75 (2H,d, J 9.0 Hz).

The following compound was obtained by the same procedures as in Example88 with the compound obtained in step 1 of Example 19 as the startingmaterial using the compound obtained in the Reference Example.

TABLE 18 Reference Example Example Structure and name Instrumental data89 72

  (4S)-4-Amino-1-[3-methyl-1-[6- [[(1R)-1-phenylethyl]amino]imidazo[1,2- b]yl]phenyl]pyrrolidin-2-one ¹H-NMR(CDCl₃) δ: 1.49 (3H, d, J = 7.3 Hz), 1.65 (2H, br s), 2.08 (3H, s), 2.61(1H, dd, J = 16.9, 6.0 Hz), 2.90 (1H, dd, J = 16.9, 8.5 Hz), 4.05-4.17(2H, m), 4.29-4.39 (1H, m), 4.70 (1H, d, J = 6.7 Hz), 4.74-4.83 (1H, m),6.44 (1H, d, J = 9.7Hz), 7.22-7.35 (6H, m), 7.43-7.50 (2H,m), 7.55-7.59(m, 1H), 7.64 (1H, d, J =9.1 Hz).

Example 90(4S)-4-Amino-1-[4-[6-[[(1R)-1-(3-fluorophenyl)ethyl]amino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

Step 1 tert-ButylN-[(3S)-1-[4-[6-[[(1R)-1-(3-fluorophenyl)ethyl]amino]imidazo[1,2-b]pyridazin-3-yl]phenyl]-5-oxopyrrolidin-3-yl]carbamate

1,4-Dioxane (10 ml) and water (3 ml) were added to the compound (0.31 g)obtained in step 1 of Example 21, the compound (0.31 g) obtained in step3 of Reference Example 65, potassium carbonate (0.43 g), and a[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethaneadduct (89 mg), and the mixture was heated to reflux for 1 hour under anitrogen atmosphere. After cooling, water was added to the reactionsolution, followed by extraction with ethyl acetate. The extract waswashed with saturated saline and then dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure. Theobtained residue was purified by silica gel column chromatography (ethylacetate-methanol) to obtain the title compound (0.31 g).

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 1.58 (3H, d, J=6.6 Hz), 2.53 (1H, dd,J=17.3, 4.3 Hz), 3.02 (1H, dd, J=17.3, 8.0 Hz), 3.78 (1H, dd, J=10.6,3.5 Hz), 4.20-4.25 (1H, m), 4.47 (1H, br s), 4.71 (1H, br s), 4.89-4.94(1H, m), 6.50 (1H, d, J=9.4 Hz), 6.97 (1H, td, J=8.6, 2.7 Hz), 7.11-7.14(1H, m), 7.21 (1H, d, J=7.8 Hz), 7.34-7.40 (1H, m), 7.60 (2H, d, J=9.0Hz), 7.68-7.74 (4H, m).

(4S)-4-Amino-1-[4-[6-[[(1R)-1-(3-fluorophenyl)ethyl]amino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

To a solution of the compound (0.31 g) obtained in the preceding step 1in methanol (3 ml), a solution of 4 N hydrochloric acid in 1,4-dioxane(5 ml) was added, and the mixture was stirred at room temperature for 1hour. The reaction solution was concentrated under reduced pressure. A 1N aqueous sodium hydroxide solution was added to the obtained residue,followed by extraction with chloroform-methanol. The extract was washedwith saturated saline and then dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure. The obtained residuewas purified by silica gel column chromatography (basic silica gel,chloroform-methanol) to obtain the title compound (0.16 g).

¹H-NMR (DMSO-d₆) δ: 1.49 (3H, d, J=7.0 Hz), 2.23 (1H, dd, J=16.8, 4.3Hz), 2.75 (1H, dd, J=16.8, 7.2 Hz), 3.17 (1H, d, J=5.1 Hz), 3.49 (1H,dd, J=9.6, 3.9 Hz), 3.66-3.68 (1H, m), 4.00 (1H, dd, J=9.6, 6.1 Hz),4.87 (1H, dq, J=5.1, 7.0 Hz), 6.79 (1H, d, J=9.4 Hz), 7.01-7.06 (1H, m),7.23-7.29 (2H, m), 7.36-7.42 (1H, m), 7.65 (2H, dd, J=5.5, 3.5 Hz), 7.77(1H, d, J=9.4 Hz), 7.81-7.86 (3H, m).

The following compounds were obtained by the same procedures as inExample 90 with the compound obtained in step 1 of Example 21 as thestarting material using the compounds obtained in the ReferenceExamples.

TABLE 19 Reference Example Example Structure and name Instrumental data91 66

  (4S)-4-Amino-1-[3-[6-[[(1R)-1-(3- fluorophenyl)ethyl]amino]imidazo[1,2-b]pyridazin-3- yl]phenyl]pyrrolidin-2-one ¹H-NMR (CDCl₃) δ: 1.58(3H, d, J = 6.6 Hz), 2.42 (1H, dd, J = 17.2, 4.9 Hz), 2.92 (1H, dd, J =17.2, 7.4 Hz), 3.58 (1H, dd, J = 9.0, 4.6 Hz), 3.81- 3.87 (1H, m), 4.10(1H, dd, J = 9.0, 7.0 Hz), 4.72 (1H, d, J = 5.9 Hz), 4.99- 5.06 (1H, m),6.49 (1H, d, J = 9.8 Hz), 6.92-6.97 (1H, m), 7.11-7.14 (1H, m), 7.19(1H, d, J = 7.8 Hz), 7.28-7.38 (2H, m), 7.53-7.56 (2H, m), 7.68 (1H, d,J = 9.4 Hz), 7.76 (1H, s), 8.09 (1H, t, J = 2.0 Hz). 92 67

  (4S)-4-Amino-1-[2-fluoro-4-[6- [[(1R)-1-(3-fluorophenyl)ethyl]amino]imidazo [1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one ¹H-NMR (CDCl₃) δ: 1.59 (3H, d, J = 7.0 Hz),2.40 (1H, dd, J = 16.8, 4.7 Hz), 2.90 (1H, dd, J = 16.8, 7.2 Hz), 3.57(1H, dd, J = 9.8, 4.3 Hz), 3.88- 3.93 (1H, m), 4.08-4.12 (1H, m), 4.87(1H, br s), 4.93-5.00 (1H, m), 6.52 (1H, d, J = 9.8 Hz), 6.91-6.96 (1H,m), 7.11 (1H, dt, J = 9.8, 2.2 Hz), 7.22 (1H, d, J = 7.8 Hz), 7.33 (1H,td, J = 7.8, 5.9 Hz), 7.42 (1H, t, J = 8.2 Hz), 7.51 (1H, dd, J = 8.4,1.8 Hz), 7.67- 7.69 (1H, m), 7.74-7.77 (2H, m). 93 68

  (4S)-4-Amino-1-[3-fluoro-4-[6- [[(1R)-1-(3-fluorophenyl)ethyl]amino]imidazo [1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one ¹H-NMR (CDCl₃) δ: 1.57 (3H, d, J = 6.6 Hz),2.45 (1H, dd, J = 17.0, 4.9 Hz), 2.95 (1H, dd, J = 17.0, 7.2 Hz), 3.61(1H, dd, J = 10.0, 4.1 Hz), 3.87- 3.91 (1H, m), 4.10 (1H, dd, J = 10.0,6.5 Hz), 4.71 (1H, d, J = 5.1 Hz), 4.85- 4.91 (1H, m), 6.52 (1H, d, J =9.4 Hz), 6.95-6.99 (1H, m), 7.09 (1H, dt, J = 9.8, 2.0 Hz), 7.19 (1H, d,J = 7.8 Hz), 7.25-7.28 (1H, m), 7.35 (1H, td, J = 8.0, 6.0 Hz),7.66-7.72 (2H, m), 7.77 (1H, t, J = 8.6 Hz), 7.85 (1H, d, J = 3.9 Hz).

Example 94(4S)-4-Amino-1-[4-[6-[benzyl(methyl)amino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

Step 1 N-Benzyl-3-bromo-N-methylimidazo[1,2-b]pyridazin-6-amine

The title compound (0.43 g) was obtained by the same procedures as instep 1 of Example 1 using N-methyl-1-phenyl-methanamine instead ofphenylmethanamine.

¹H-NMR (CDCl₃) δ: 3.20 (3H, s), 4.76 (2H, s), 6.73 (1H, d, J=9.7 Hz),7.27-7.36 (5H, m), 7.51 (1H, s), 7.63 (1H, d, J=9.7 Hz).

Step 2 tert-ButylN-[(3S)-1-[4-[6-[benzyl(methyl)amino]imidazo[1,2-b]pyridazin-3-yl]phenyl]-5-oxopyrrolidin-3-yl]carbamate

The title compound (0.36 g) was obtained by the same procedures as instep 1 of Example 72 with the compound (0.22 g) obtained in thepreceding step 1 and the compound (0.33 g) obtained in step 3 ofReference Example 65 as starting materials.

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.51 (1H, dd, J=17.2, 4.5 Hz), 3.00 (1H,dd, J=17.5, 7.9 Hz), 3.22 (3H, s), 3.76 (1H, dd, J=10.3, 3.0 Hz),4.13-4.23 (1H, m), 4.44 (1H, br s), 4.76 (2H, s), 4.88 (1H, br s), 6.77(1H, d, J=10.3 Hz), 7.22-7.30 (3H, m), 7.32-7.38 (2H, m), 7.65 (2H, d,J=9.1 Hz), 7.73 (1H, d, J=9.7 Hz), 7.83 (1H, s), 8.05-8.09 (2H, m).

Step 3(4S)-4-Amino-1-[4-[6-[benzyl(methyl)amino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

The title compound (0.18 g) was obtained by the same procedures as instep 2 of Example 72 with the compound (0.36 g) obtained in thepreceding step 2 as the starting material.

¹H-NMR (CDCl₃) δ: 2.43 (1H, dd, J=16.9, 4.8 Hz), 2.93 (1H, dd, J=17.2,7.6 Hz), 3.22 (3H, s), 3.59 (1H, dd, J=9.7, 4.2 Hz), 3.82-3.88 (1H, m),4.10 (1H, dd, J=10.0, 6.3 Hz), 4.76 (2H, s), 6.77 (1H, d, J=10.3 Hz),7.25-7.31 (3H, m), 7.34-7.37 (2H, m), 7.67 (2H, d, J=9.1 Hz), 7.73 (1H,d, J=9.7 Hz), 7.83 (1H, s), 8.07 (2H, d, J=8.5 Hz).

The following compound was obtained by the same procedures as in Example94.

TABLE 20 Reference Example Example Structure and name Instrumental data95 65

  (4S)-4-Amino-1-[4-[6- [benzo(ethyl)amino]imidazo[1,2- b]pyridazin-3-yl]phenyl]pyrrolidin-2-one ¹H-NMR (CDCl₃) δ: 1.29 (3H, t, J = 7.3 Hz),2.42 (1H, dd, J = 17.2, 5.1 Hz), 2.93 (1H, dd, J = 16.9, 7.3 Hz), 3.59(1H, dd, J = 9.7, 4.2 Hz), 3.66 (2H, q, J = 7.1 Hz), 3.82-3.88 (1H, m),4.08-4.12 (1H, m), 4.74 (2H, s), 6.71 (1H, d, J = 9.7 Hz), 7.26-7.31(3H, m), 7.32-7.37 (2H, m), 7.63 (2H, d, J = 8.5 Hz), 7.71 (1H, d, J =9.7 Hz), 7.80 (1H, s), 8.00 (2H, d, J = 8.5 Hz).

Example 964-Amino-1-[4-[6-[(3-chlorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

Step 1 1-(3-Chlorophenyl)-N-methylmethanamine

To a solution of methylamine (2.0 M solution in tetrahydrofuran, 30 ml)in N,N-dimethylformamide (30 ml), 3-chlorobenzyl chloride (2.5 ml) wasadded, and the mixture was stirred at room temperature for 4.5 hours.Water was added to the reaction solution, followed by extraction withethyl acetate. The extract was washed with water and saturated saline inthis order and then dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure to obtain a crude product of thetitle compound, which was used in the next reaction without beingpurified.

¹H-NMR (CDCl₃) δ: 2.42 (3H, s), 3.69 (2H, s), 7.14-7.36 (4H, m).

Step 23-Bromo-N-[(3-chlorophenyl)methyl]-N-methylimidazo[1,2-b]pyridazin-6-amine

The title compound (1.7 g) was obtained by the same procedures as instep 1 of Example 1 using the compound obtained in the preceding step 1instead of phenylmethanamine.

¹H-NMR (CDCl₃) δ: 3.17 (3H, s), 4.71 (2H, s), 6.69 (1H, d, J=9.8 Hz),7.16-7.32 (4H, m), 7.49 (1H, s), 7.63 (1H, d, J=9.8 Hz).

Step 3 tert-ButylN-[1-[4-[6-[(3-chlorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]-5-oxopyrrolidin-3-yl]carbamate

The title compound (0.26 g) was obtained by the same procedures as instep 1 of Example 72 with the compound (0.20 g) obtained in thepreceding step 2 and the compound (0.30 g) obtained in step 3 ofReference Example 61 as starting materials.

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.52 (1H, dd, J=17.4, 4.5 Hz), 3.01 (1H,dd, J=17.4, 8.0 Hz), 3.23 (3H, s), 3.75-3.81 (1H, m), 4.18-4.25 (1H, m),4.45 (1H, br s), 4.73 (2H, s), 4.95 (1H, br s), 6.76 (1H, d, J=9.8 Hz),7.13-7.17 (1H, m), 7.26-7.33 (3H, m), 7.65 (2H, d, J=8.6 Hz), 7.77 (1H,d, J=9.8 Hz), 7.83 (1H, s), 8.00 (2H, d, J=9.0 Hz).

Step 44-Amino-1-[4-[6-[(3-chlorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

The title compound (0.16 g) was obtained by the same procedures as instep 2 of Example 72 with the compound (0.26 g) obtained in thepreceding step 3 as the starting material.

¹H-NMR (CDCl₃) δ: 2.39 (1H, dd, J=17.2, 5.1 Hz), 2.89 (1H, dd, J=17.2,7.4 Hz), 3.20 (3H, s), 3.56 (1H, dd, J=9.8, 4.3 Hz), 3.79-3.85 (1H, m),4.05-4.09 (1H, m), 4.69 (2H, s), 6.72 (1H, d, J=10.2 Hz), 7.11-7.13 (1H,m), 7.20-7.27 (3H, m), 7.63 (2H, d, J=9.0 Hz), 7.73 (1H, d, J=9.8 Hz),7.79 (1H, s), 7.96 (2H, d, J=9.0 Hz).

The following compounds were obtained by the same procedures as inExample 96

TABLE 21 Reference Example Example Structure and name Instrumental data 97 65

  (4S)-4-Amino-1-[4-[6-[(2,5- difluorophenyl)methyl-methylamino]imidazo[1,2- b]pyridazin-3- yl]phenyl]pyrrolidin-2-one¹H-NMR (CDCl₃) δ: 2.42 (1H, dd, J = 17.2, 5.1 Hz), 2.93 (1H, dd, J =16.9, 7.3 Hz), 3.25 (3H, s), 3.59 (1H, dd, J = 9.7, 4.2 Hz), 3.82-3.88(1H, m), 4.08-4.13 (1H, m), 4.77 (2H, s), 6.76 (1H, d, J = 9.7 Hz),6.89-6.97 (2H, m), 7.05-7.11 (1H, m), 7.66 (2H, d, J = 9.1 Hz), 7.78(1H, dd, J = 10.3 Hz), 7.83 (s, 1H), 8.01 (2H, d, J = 9.1 Hz). 98 65

  (4S)-4-Amino-1-[4-[6-[(2,3- difluorophenyl)methyl-methylamino]imidazo[1,2- b]pyridazin-3- yl]phenyl]pyrrolidin-2-one¹H-NMR (CDCl₃) δ: 2.22 (1H, dd, J = 16.9, 4.2 Hz), 2.74 (1H, dd, J =16.3, 7.3 Hz), 3.25 (3H, s), 3.44-3.48 (1H, m), 3.63-3.68 (1H, m), 3.98(1H, dd, J = 9.7, 6.0 Hz), 4.91 (2H, s), 7.03-7.07 (1H, m), 7.11-7.16(2H, m), 7.30-7.37 (1H, m), 7.67 (2H, d, J = 9.1 Hz), 7.91-7.95 (2H, m),8.02 (2H, d, J = 9.1 Hz). 99 65

  (4S)-4-Amino-1-[4-[6-[(2-chloro- 5-fluorophenyl)methyl-methylamino]imidazo[1,2- b]pyridazin-3- yl]phenyl]pyrrolidin-2-one¹H-NMR (CDCl₃) δ: 2.43 (1H, dd, J = 16.9, 4.8 Hz), 2.93 (1H, dd, J =17.2, 7.6 Hz), 3.30 (3H, s), 3.59 (1H, dd, J = 10.0, 3.9 Hz), 3.84-3.89(1H, m), 4.10 (1H, dd, J = 9.7, 6.7 Hz), 4.78 (2H, s), 6.71 (1H, d, J =10.3 Hz), 6.87-6.97 (2H, m), 7.42 (1H, dd, J = 8.5, 4.8 Hz), 7.64 (2H,d, J = 8.5 Hz), 7.78 (1H, d, J = 9.7 Hz), 7.85 (1H, s), 7.98 (2H, d, J =9.1 Hz). 100 65

  (4S)-4-Amino-1-[4-[6-[ethyl[(3- fluorophenyl)methyl]amino]imidazo[1,2-b][yridazin-3- yl]phenyl]pyrrolidin-2-one ¹H-NMR (CDCl₃) δ:1.26 (3H, t, J = 7.0 Hz), 2.39 (1H, dd, J = 17.0, 4.9 Hz), 2.89 (1H, dd,J = 16.8, 7.4 Hz), 3.55 (1H, dd, J = 9.8, 3.9 Hz), 3.62 (2H, q, J = 7.0Hz), 3.79-3.85 (1H, m), 4.06 (1H, dd, J = 9.8, 6.3 Hz), 4.68 (2H, s),6.68 (1H, d, J = 10.2 Hz), 6.90-6.99 (2H, m), 7.03- 7.05 (1H, m),7.26-7.32 (1H, m), 7.59 (2H, d, J = 9.0 Hz), 7.70 (1H, dd, J = 9.8 Hz),7.77 (1H, s), 7.89 (2H, d, J = 9.0 Hz).

Example 1013-[[3-[4-[(4S)-4-Amino-2-oxopyrrolidin-1-yl]phenyl]imidazo[1,2-b]pyridazin-6-yl]oxymethyl]benzonitrile

Step 1 3-[(3-Bromoimidazo[1,2-b]pyridazin-6-yl)oxymethyl]benzonitrile

The title compound (1.75 g) was obtained by the same procedures as instep 1 of Example 11 using 3-(hydroxymethyl)benzonitrile (1.50 g)instead of 3-fluorobenzyl alcohol.

¹H-NMR (CDCl₃) δ: 5.45 (2H, s), 6.75 (1H, d, J=9.8 Hz), 7.49 (1H, t,J=7.8 Hz), 7.59 (1H, s), 7.62 (1H, dt, J=7.8, 1.4 Hz), 7.75-7.79 (2H,m), 7.87 (1H, t, J=1.4 Hz).

ESI-MS (m/z): 329, 331 (M+H)⁺.

Step 2 tert-ButylN-[(3S)-1-[4-[6-[(3-cyanophenyl)methoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]-5-oxopyrrolidin-3-yl]carbamate

The title compound (286 mg) was obtained by the same procedures as instep 1 of Example 72 using the compound (250 mg) obtained in thepreceding step 1 and the compound (306 mg) obtained in step 3 ofReference Example 65.

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.55 (1H, dd, J=17.6, 4.3 Hz), 3.02 (1H,dd, J=17.6, 7.8 Hz), 3.82 (1H, dd, J=10.4, 3.3 Hz), 4.26 (1H, dd,J=10.4, 6.8 Hz), 4.44-4.49 (1H, m), 4.98-5.02 (1H, m), 5.43 (2H, s),6.81 (1H, d, J=9.4 Hz), 7.52 (1H, t, J=7.8 Hz), 7.61-7.64 (1H, m),7.70-7.72 (1H, m), 7.75-7.78 (3H, m), 7.87 (1H, s), 7.88-7.93 (3H, m).

ESI-MS (m/z): 525 (M+H)⁺.

Step 33-[[3-[4-[(4S)-4-Amino-2-oxopyrrolidin-1-yl]phenyl]imidazo[1,2-b]pyridazin-6-yl]oxymethyl]benzonitrile

The title compound (194 mg) was obtained by the same procedures as instep 2 of Example 79 using the compound (286 mg) obtained in thepreceding step 2.

¹H-NMR (CDCl₃) δ: 1.48-1.63 (2H, m), 2.45 (1H, dd, J=16.8, 4.7 Hz), 2.95(1H, dd, J=16.8, 7.4 Hz), 3.65 (1H, dd, J=9.8, 3.9 Hz), 3.85-3.91 (1H,m), 4.16 (1H, dd, J=9.8, 6.7 Hz), 5.43 (2H, s), 6.80 (1H, d, J=9.8 Hz),7.53 (1H, t, J=7.8 Hz), 7.64 (1H, dt, J=7.8, 1.4 Hz), 7.72 (1H, dt,J=7.8, 1.4 Hz), 7.75-7.79 (3H, m), 7.86-7.91 (4H, m).

ESI-MS (m/z): 425 (M+H)⁺.

The following compounds were obtained by the same procedures as inExample 101.

TABLE 22 Reference Example Example Structure and name Instrumental data102 65

  (4S)-4-Amino-1-[4-[6-[1-(2,3- difluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3- yl]phenyl]pyrrolidin-2-one ¹H-NMR (CDCl₃) δ: 1.72(3H, d, J = 6.7 Hz), 2.45 (1H, dd, J = 17.2, 5.1 Hz), 2.95 (1H, dd, J =17.2, 7.6 Hz), 3.61-3.67 (1H, m), 3.85-3.91 (1H, m), 4.13-4.18 (1H, m),6.26 (1H, q, J = 6.7 Hz), 6.79 (1H, d, J = 9.7 Hz), 7.02-7.11 (2H, m),7.18 (1H, t, J = 6.3 Hz), 7.70 (2H, d, J = 8.5 Hz), 7.76 (2H, d, J = 8.5Hz), 7.84 (1H, s), 7.86 (1H, d, J = 9.7 Hz). ESI-MS (m/z): 450 (M + H)⁺.103 65

  (4S)-4-Amino-1-[4-[6-[(5- fluoro-2- methylphenyl)methoxy]imidazo[1,2-b]pyriazin-3- yl]phenyl]pyrrolidin-2-one ¹H-NMR (CDCl₃) δ:1.54 (2H, br s), 2.36 (3H, s), 2.44 (1H, dd, J = 16.9, 4.8 Hz), 2.95(1H, dd, J = 16.9, 7.3 Hz), 3.62 (1H, dd, J = 10.0, 4.2 Hz), 3.85-3.91(1H, m), 4.13 (1H, dd, J = 10.0, 6.7 Hz), 5.38 (2H, s), 6.79 (1H, d, J =9.7 Hz), 6.97 (1H, td, J = 8.5, 3.0 Hz), 7.16 (1H, dd, J = 9.7, 3.0 Hz),7.22 (1H, dd, J = 8.5, 5.4 Hz), 7.72- 7.75 (2H, m), 7.89 (2H, t, J = 4.8Hz), 7.95-7.99 (2H, m). ESI-MS (m/z): 432 (M + H)⁺. 104 65

  (4S)-4-Amino-1-[4-[6-[1-(2,5- difluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3- yl]phenyl]pyrrolidin-2-one ¹H-NMR (CDCl₃) δ: 1.70(3H, d, J = 6.7 Hz), 2.45 (1H, dd, J = 16.9, 4.8 Hz), 2.95 (1H, dd, J =17.2, 7.6 Hz), 3.62 (1H, dd, J = 10.0, 3.9 Hz), 3.85-3.92 (1H, m), 4.11-4.16 (1H, m), 6.25 (1H, q, J = 6.4 Hz), 6.80 (1H, d, J = 9.1 Hz),6.90-6.96 (1H, m), 7.08-7.14 (2H, m), 7.68 (2H, d, J = 9.1 Hz),7.79-7.88 (4H, m). 105 65

  (4S)-4-Amino-1-[4-[6-(1- thiazol-2- ylethoxy)imidazo[1,2-b]pyridazin-3- yl]phenyl]pyrrolidin-2-one ¹H-NMR (DMSO-d₆) δ: 1.81 (3H,d, J = 6.7 Hz), 1.95-2.10 (2H, br m), 2.20-2.27 (1H, m), 2.72-2.79 (1H,m), 3.47-3.53 (1H, m), 3.63-3.69 (1H, m), 3.99-4.05 (1H, m), 6.42 (1H,q, J = 6.7 Hz), 7.03 (1H, d, J = 9.7 Hz), 7.72 (1H, d, J = 3.6 Hz),7.74-7.78 (2H, m), 7.82-7.84 (1H, m), 8.00-8.04 (2H, m), 8.10 (1H, s),8.13 (1H, d, J = 9.7 Hz). ESI-MS (m/z): 421 (M + H)⁺.

Example 106(4S)-4-Amino-1-[4-[6-[(1-(2,5-difluoro-3-pyridyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

Step 13-Bromo-6-[1-(2,5-difluoro-3-pyridyl)ethoxy]imidazo[1,2-b]pyridazine

The title compound (0.74 g) was obtained by the same procedures as instep 1 of Example 11 using the compound (0.35 g) obtained in step 5 ofReference Example 54 instead of 3-fluorobenzyl alcohol.

¹H-NMR (CDCl₃) δ: 1.76 (3H, d, J=6.7 Hz), 6.23 (1H, q, J=6.7 Hz), 6.78(1H, d, J=9.7 Hz), 7.58 (1H, s), 7.65 (1H, td, J=7.9, 3.0 Hz), 7.80 (1H,d, J=9.7 Hz), 7.96-7.98 (1H, m).

Step 2 tert-ButylN-[(3S)-1-[4-[6-[1-(2,5-difluoro-3-pyridyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]-5-oxopyrrolidin-3-yl]carbamate

The title compound (154 mg) was obtained by the same procedures as instep 1 of Example 72 with the compound (290 mg) obtained in thepreceding step 1 as the starting material using the compound (329 mg)obtained in step 3 of Reference Example 65.

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 1.72 (3H, d, J=6.7 Hz), 2.58 (1H, dd,J=17.5, 4.8 Hz), 3.01 (1H, dd, J=17.5, 8.5 Hz), 3.81 (1H, dd, J=10.3,4.2 Hz), 4.19-4.28 (1H, m), 4.43-4.53 (1H, m), 5.41 (1H, d, J=7.3 Hz),6.13 (1H, q, J=6.7 Hz), 6.80 (1H, d, J=9.7 Hz), 7.58 (1H, td, J=7.3, 3.0Hz), 7.65-7.73 (4H, m), 7.84 (1H, s), 7.89 (1H, d, J=9.7 Hz), 7.93-7.95(1H, m).

ESI-MS (m/z): 551 (M+H)⁺.

Step 3(4S)-4-Amino-1-[4-[6-[1-(2,5-difluoro-3-pyridyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

The title compound (81 mg) was obtained by the same procedures as instep 2 of Example 79 using the compound (154 mg) obtained in thepreceding step 2.

¹H-NMR (CDCl₃) δ: 1.73 (3H, d, J=6.7 Hz), 2.45 (1H, dd, J=16.9, 5.1 Hz),2.95 (1H, dd, J=16.9, 7.3 Hz), 3.65 (1H, dd, J=10.0, 3.9 Hz), 3.85-3.91(1H, m), 4.16 (1H, dd, J=10.0, 6.3 Hz), 6.16 (1H, q, J=6.7 Hz), 6.81(1H, d, J=9.7 Hz), 7.58 (1H, td, J=7.3, 3.0 Hz), 7.69-7.75 (4H, m), 7.86(1H, s), 7.90 (1H, d, J=9.7 Hz), 7.95-7.96 (1H, m).

ESI-MS (m/z): 451 (M+H)⁺.

The following compounds were obtained by the same procedures as inExample 106.

TABLE 23-1 Reference Example Example No. No. Structure and nameInstrumental data 107 56 65

  (4S)-4-Amino-1-[4-[6-[(1-(5- fluoro-3- pyridyl)ethoxy]imidazo[1,2-b]pyridazin-3- yl]phenyl]pyrrolidin-2-one ¹H-NMR (CDCl₃) δ: 1.48 (9H,s), 1.74 (3H, d, J = 6.6 Hz), 2.55 (1H, dd, J = 17.2, 4.3 Hz), 3.03 (1H,dd, J = 17.4, 8.0 Hz), 3.82 (1H, dd, J = 10.0, 3.3 Hz), 4.23-4.28 (1H,m), 4.44-4.51 (1H, m), 4.92 (1H, br s), 6.03 (1H, q, J = 6.6 Hz), 6.79(1H, d, J = 9.4 Hz), 7.46-7.50 (1H, m), 7.71-7.75 (4H, m), 7.83 (1H, s),7.88 (1H, d, J = 9.4 Hz), 8.41 (1H, d, J = 2.7 Hz), 8.53 (1H, t, J = 1.6Hz). ESI-MS (m/z): 533 (M + H)⁺. 108 56 71

  (4S)-1-[4-[6-[(1R)-1-(5-Fluoro- 3-pyridyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]-4- (methylamino)pyrrolidin-2-one ¹H-NMR (CDCl₃)δ: 1.74 (3H, d, J = 6.7 Hz), 2.50-2.56 (1H, m), 2.52 (3H, s), 2.91 (1H,dd, J = 17.2, 7.6 Hz), 3.53- 3.59 (1H, m), 3.74 (1H, dd, J = 9.7, 4.2Hz), 4.11 (1H, dd, J = 9.7, 6.7 Hz), 6.03 (1H, q, J = 6.7 Hz), 6.78 (1H,d, J = 9.7 Hz), 7.48 (1H, dt, J = 9.1, 2.1 Hz), 7.70- 7.75 (4H, m), 7.82(1H, s), 7.87 (1H, d, J = 9.7 Hz), 8.41 (1H, d, J = 2.4 Hz), 8.53 (1H,s). ESI-MS (m/z): 447 (M + H)⁺.

TABLE 23-2 109 56 67

  (4S)-4-Amino-1-[2-fluoro-4-[6- [(1R)-1-(5-fluoro-3-pyridyl)ethoxy]imidazo[1,2- b]pyridazin-3-yl]phenyl]pyrrolidin- 2-one¹H-NMR (CDCl₃) δ: 1.75 (3H, d, J = 6.7 Hz), 2.40 (1H, dd, J = 17.0, 5.4Hz), 2.90 (1H, dd, J = 17.0, 7.6 Hz), 3.61 (1H, dd, J = 10.3, 4.2 Hz),3.88-3.94 (1H, m), 4.10- 4.14 (1H, m), 6.07 (1H, q, J = 6.7 Hz), 6.84(1H, d, J = 9.7 Hz), 7.47-7.59 (3H, m), 7.70 (1H, dd, J = 12.7, 1.8 Hz),7.86 (1H, s), 7.90 (1H, d, J = 9.7 Hz), 8.41 (1H, d, J = 2.4 Hz),8.55-8.56 (1H, m). ESI-MS (m/z): 451 (M + H)⁺. 110 56 68

  (4S)-4-Amino-1-[3-fluoro-4-[6- [(1R)-1-(5-fluoro-3-pyridyl)ethoxy]imidazo[1,2- b]pyridazin-3-yl]phenyl]pyrrolidin- 2-one¹H-NMR (CDCl₃) δ: 1.71 (3H, d, J = 6.7 Hz), 2.46 (1H, dd, J = 16.9, 4.8Hz), 2.96 (1H, dd, J = 16.9, 6.7 Hz), 3.64 (1H, dd, J = 10.0, 3.9 Hz),3.88-3.92 (1H, m), 4.13 (1H, dd, J = 10.0, 7.0 Hz), 5.96 (1H, q, J = 6.7Hz), 6.80 (1H, d, J = 9.7 Hz), 7.40- 7.44 (2H, m), 7.66 (1H, t, J = 8.2Hz), 7.77 (1H, dd, J = 12.7, 1.8 Hz), 7.87-7.90 (2H, m), 8.40 (1H, d, J= 3.0 Hz), 8.47 (1H, s). ESI-MS (m/z): 451 (M + H)⁺. 111 56 74

  (4S)-4-Amino-1-[4-[6-[(1-(5- fluoro-3- pyridyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]-2- methylphenyl]pyrrolidin-2-one ¹H-NMR (CDCl₃) δ:1.73 (3H, d, J = 6.7 Hz), 2.34 (3H, s), 2.40 (1H, dd, J = 16.9, 4.8 Hz),2.91 (1H, dd, J = 16.9, 7.3 Hz), 3.48 (1H, dd, J = 9.7, 3.6 Hz),3.91-3.97 (1H, m), 4.02 (1H, dd, J = 9.7, 6.7 Hz), 6.05 (1H, q, J = 6.7Hz), 6.80 (1H, d, J = 9.7 Hz), 7.25-7.28 (1H, m), 7.46-7.53 (2H, m),7.67 (1H, br s), 7.81 (1H, s), 7.88 (1H, d, J = 9.7 Hz), 8.42 (1H, d, J= 2.4 Hz), 8.53 (1H, br s). ESI-MS (m/z): 447 (M + H)⁺. 112 57 65

  (4S)-4-Amino-1-[4-[6-[(1-(5- chloro-3- pyridyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin- 2-one ¹H-NMR (CDCl₃) δ: 1.73 (3H, d,J = 6.7 Hz), 2.46 (1H, dd, J = 16.9, 4.8 Hz), 2.95 (1H, dd, J = 16.9,7.3 Hz), 3.65 (1H, dd, J = 10.0, 4.2 Hz), 3.86-3.92 (1H, m), 4.15 (1H,dd, J = 10.0, 6.3 Hz), 5.98 (1H, q, J = 6.7 Hz), 6.78 (1H, d, J = 9.7Hz), 7.70- 7.77 (5H, m), 7.82 (1H, s), 7.87 (1H, d, J = 9.7 Hz), 8.51(1H, d, J = 2.0 Hz), 8.58 (1H, d, J = 2.0 Hz). ESI-MS (m/z): 449, 451(M + H)⁺.

TABLE 23-3 113 55 65

  (4S)-4-Amino-1-[4-[6-[1-(5-chloro- 1-methylpyrazol-3-yl)ethoxy]imidazo[1,2-b]pyridazin- 3-yl]phenyl]pyrrolidin-2-one ¹H-NMR(CDCl₃) δ: 1.47 (9H, s), 1.74 (3H, d, J = 6.7 Hz), 2.53 (1H, dd, J =17.5, 4.8 Hz), 3.02 (1H, dd, J = 17.5, 7.9 Hz), 3.79-3.84 (1H, m), 3.83(3H, s), 4.24 (1H, dd, J = 10.3, 6.7 Hz), 4.46 (1H, br s), 4.88 (1H, brs), 6.11 (1H, q, J = 6.7 Hz), 6.25 (1H, s), 6.74 (1H, d, J = 9.7 Hz),7.72-7.76 (2H, m), 7.83 (1H, d, J = 9.7 Hz), 7.89 (1H, s), 8.05-8.09(2H, m). ESI-MS (m/z): 552 (M + H)⁺. 114 58 65

  (4S)-4-Amino-1-[4-[6-[1-[5-fluoro- 2-(triazol-2-yl)phenyl]ethoxy]imidazo[1,2- b]pyridazin-3-yl]phenyl]pyrrolidin- 2-one¹H-NMR (CDCl₃) δ: 1.62 (3H, d, J = 6.1 Hz), 2.46 (1H, dd, J = 17.1, 4.9Hz), 2.96 (1H, ddd, J = 17.1, 7.5, 1.7 Hz), 3.59 (1H, dd, J = 9.8, 3.7Hz), 3.85-3.92 (1H, m), 4.08-4.13 (1H, m), 6.76-6.81 (2H, m), 7.08-7.13(1H, m), 7.45 (1H, dd, J = 9.8, 3.1 Hz), 7.60-7.64 (2H, m), 7.77 (1H,dd, J = 9.2, 5.2 Hz), 7.85-7.89 (4H, m), 7.96- 7.97 (2H, m). ESI-MS(m/z): 499 (M + H)⁺. 115 59 65

  (4S)-4-Amino-1-[4-[6-[1-[1- (difluoromethyl)triazol-4-yl]ethoxy]imidazo[1,2-b]pyridazin- 3-yl]phenyl]pyrrolidin-2-one ¹H-NMR(DMSO-d₆) δ: 1.81 (3H, d, J = 6.5 Hz), 1.90-2.02 (2H, br m), 2.24 (1H,dd, J = 16.6, 4.1 Hz), 2.76 (1H, dd, J = 16.6, 7.0 Hz), 3.47-3.52 (1H,m), 3.64- 3.70 (1H, m), 3.98-4.04 (1H, m), 6.36 (1H, q, J = 6.5 Hz),6.95 (1H, d, J = 9.8 Hz), 7.76-7.81 (2H, m), 8.05-8.12 (4H, m), 8.23(1H, t, J = 58.3 Hz), 8.83 (1H, s). ESI-MS (m/z): 455 (M + H)⁺. 116 6065

  5-[1-[3-[4-[(4S)-4-Amino-2- oxopyrrolidin-1-yl]phenyl]imidazo[1,2-b]pyridazin- 6-yl]oxyethyl]-2-methyl pyrazole-3-carbonitrile ¹H-NMR (DMSO-d₆) δ: 1.71 (3H, d, J = 6.5 Hz), 1.89-1.97(2H, br m), 2.24 (1H, dd, J = 16.6, 4.1 Hz), 2.76 (1H, dd, J = 16.6, 7.0Hz), 3.49-3.53 (1H, m), 3.64- 3.69 (1H, m), 4.00 (3H, s), 4.01-4.05 (1H,m), 6.17 (1H, q, J = 6.5 Hz), 6.92 (1H, d, J = 9.8 Hz), 7.24 (1H, s),7.78-7.82 (2H, m), 8.07-8.14 (4H, m). ESI-MS (m/z): 443 (M + H)⁺.

Example 117(4S)-4-Amino-1-[4-[6-[methyl(3-pyridylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

Step 1 N-Methyl-1-(3-pyridyl)methanamine

To a solution of 3-pyridine-carboxaldehyde (0.24 g) in methanol,methylamine (2.0 M solution in tetrahydrofuran, 6 ml) was added, and themixture was stirred at room temperature for 23 hours. Then, sodiumborohydride (0.22 g) was added thereto, and the mixture was stirred for1 hour. The reaction solution was concentrated under reduced pressure.The residue was partially purified on a reverse-phase silica gel column.A crude product was obtained by decantation and directly used in thenext reaction.

¹H-NMR (CD₃OD) δ: 3.75 (3H, s), 4.87 (2H, s), 7.33-7.46 (1H, m),7.78-7.89 (1H, m), 8.44-8.59 (2H, m).

Step 23-Bromo-N-methyl-N-(3-pyridylmethyl)imidazo[1,2-b]pyridazin-6-amine

The title compound (0.07 g) was obtained by the same procedures as instep 1 of Example 1 using the compound obtained in the preceding step 1instead of phenylmethanamine.

ESI-MS (m/z): 318 (M+H)⁺.

Step 3 tert-ButylN-[(3S)-1-[4-[6-[methyl(3-pyridylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl]phenyl]-5-oxopyrrolidin-3-yl]carbamate

The title compound (0.06 g) was obtained by the same procedures as instep 1 of Example 72 with the compound (0.07 g) obtained in thepreceding step 2 and the compound (0.11 g) obtained in step 3 ofReference Example 65 as starting materials.

ESI-MS (m/z): 514 (M+H)⁺.

Step 4(4S)-4-Amino-1-[4-[6-[methyl(3-pyridylmethyl)amino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

The title compound (0.037 g) was obtained by the same procedures as instep 2 of Example 72 with the compound (0.06 g) obtained in thepreceding step 3 as the starting material.

¹H-NMR (CDCl₃) δ: 2.42 (1H, dd, J=16.9, 4.8 Hz), 2.92 (1H, dd, J=16.9,7.3 Hz), 3.22 (3H, s), 3.59 (1H, dd, J=9.7, 4.2 Hz), 3.82-3.88 (1H, m),4.10 (1H, dd, J=9.7, 6.7 Hz), 4.79 (2H, s), 6.79 (1H, d, J=9.7 Hz),7.27-7.30 (1H, m), 7.59-7.62 (1H, m), 7.65 (2H, d, J=9.1 Hz), 7.78 (1H,d, J=10.3 Hz), 7.83 (1H, s), 7.98 (2H, d, J=9.1 Hz), 8.53-8.59 (2H, m).

The following compounds were obtained by the same procedures as inExample 117.

TABLE 24-1 Reference Example Example Structure and name Instrumentaldata 118 65

  (4S)-4-Amino-1-[4-[6-[(5-fluoro- 3-pyridyl)methyl-methylamino]imidazo[1,2- b]pyridazin-3- yl]phenyl]pyrrolidin-2-one¹H-NMR (CDCl₃) δ: 2.42 (1H, dd, J = 16.9, 4.8 Hz), 2.93 (1H, dd, J =16.9, 7.3 Hz), 3.24 (3H, s), 3.59 (1H, dd, J = 9.7, 4.2 Hz), 3.83-3.89(1H, m), 4.08-4.15 (1H, m), 4.80 (2H, s), 6.79 (1H, d, J = 10.3 Hz),7.31-7.36 (1H, m), 7.66 (2H, d J = 9.1 Hz), 7.78-7.86 (2H, m), 7.93 (2H,d, J = 9.1 Hz), 8.39-8.42 (2H, m). 119 75

  4-Amino-1-[4-[6-[(5-fluoro-3- pyridyl)methyl- methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]-4- methylpyrrolidin-2-one ¹H-NMR (CDCl₃) δ:1.46 (3H, s), 2.57 (1H, d, J = 16.3 Hz), 2.68 (1H, d, J = 16.9 Hz), 3.23(3H, s), 3.69 (1H, d, J = 9.7 Hz), 3.79 (1H, d, J = 9.7 Hz), 4.80 (2H,s), 6.78 (1H, d, J = 10.3 Hz), 7.31-7.36 (1H, m), 7.65 (2H, d, J = 9.1Hz), 7.79- 7.84 (2H, m), 7.93 (2H, d, J = 8.5 Hz), 8.40-8.41 (2H, m).120 65

  (4S)-4-Amino-1-[4-[6-[(3,5- difluorophenyl)methyl-methylamino]imidazo[1,2- b]pyridazin-3- yl]phenyl]pyrrolidin-2-one¹H-NMR (DMSO-d₆) δ: 1.93 (2H, br s), 2.22 (1H, dd, J = 16.3, 4.2 Hz),2.74 (1H, dd, J = 16.3, 7.3 Hz), 3.26 (3H, s), 3.47 (1H, dd, J = 9.7,3.6 Hz), 3.62-3.69 (1H, m), 3.98 (1H, dd, J = 9.7, 6.0 Hz), 4.82 (2H,s), 6.99-7.15 (3H, m), 7.09 (1H, d, J = 10.3 Hz), 7.66-7.71 (2H, m),7.92 (1H, d, J = 10.3 Hz), 7.95 (1H, s), 8.02-8.07 (2H, m). ESI-MS(m/z): 449 (M + H)⁺. 121 65

  3-[[[3-[4-[(4S)-4-Amino-2- oxopyrrolidin-1- yl]phenyl]imidazo[1,2-b]pyridazin-6-yl]- methylamino]methyl]benzonitrile ¹H-NMR (DMSO-d₆) δ:1.92-2.10 (2H, br m), 2.22 (1H, dd, J = 16.6, 4.2 Hz), 2.74 (1H, dd, J =16.6, 7.3 Hz), 3.26 (3H, s), 3.48 (1H, dd, J = 9.7, 3.6 Hz), 3.62- 3.68(1H, m), 3.99 (1H, dd, J = 9.7, 6.0 Hz), 4.86 (2H, s), 7.11 (1H, d, J =9.7 Hz), 7.55 (1H, t, J = 7.9 Hz), 7.61-7.80 (5H, m), 7.91 (1H, d, J =9.7 Hz), 7.93 (1H, s), 8.01-8.05 (2H, m). ESI-MS (m/z): 438 (M + H)⁺.

TABLE 24-2 122 65

  (4S)-4-Amino-1-[4-[6-[(5-chloro-3- pyridyl)methyl-methylamino]imidazo[1,2- b]pyridazin-3-yl]phenyl]pyrrolidin- 2-one¹H-NMR (CDCl₃) δ: 2.42 (1H, dd, J = 16.9, 4.8 Hz), 2.93 (1H, dd, J =17.2, 7.6 Hz), 3.24 (3H, s), 3.59 (1H, dd, J = 9.7, 4.2 Hz), 3.83-3.89(1H, m), 4.11 (1H, dd, J = 10.0, 6.3 Hz), 4.77 (2H, s), 6.79 (1H, d, J =9.7 Hz), 7.60-7.62 (1H, m), 7.67 (2H, d, J = 9.1 Hz), 7.80-7.83 (2H, m),7.92 (2H, d, J = 8.5 Hz), 8.46-8.51 (2H, m). 123 75

  4-Amino-1-[4-[6-[(5-chloro-3- pyridyl)methyl- methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]-4- methylpyrrolidin-2-one ¹H-NMR (CDCl₃) δ:1.47 (3H, s), 2.57 (1H, d, J = 16.9 Hz), 2.69 (1H, d, J = 16.9 Hz), 3.24(3H, s), 3.69 (1H, d, J = 9.7 Hz), 3.80 (1H, d, J = 9.7 Hz), 4.77 (2H,s), 6.79 (1H, d, J = 9.7 Hz), 7.60-7.61 (1H, m), 7.65 (2H, d, J = 9.1Hz), 7.80-7.83 (2H, m), 7.92 (2H, d, J = 8.5 Hz), 8.45-8.51 (2H, m). 12478

  4-Amino-1-[4-[6-[(5-fluoro-3- pyridyl)methyl- methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]-4- methylpyrrolidin-2-one ¹H-NMR (CDCl₃) δ:1.46 (3H, s), 2.57 (1H, d, J = 16.9 Hz), 2.68 (1H, d, J = 16.9 Hz), 3.23(3H, s), 3.69 (1H, d, J = 9.7 Hz), 3.80 (1H, d, J = 9.7 Hz), 4.81 (2H,s), 6.79 (1H, d, J = 9.7 Hz), 7.32-7.35 (1H, m), 7.65 (2H, d, J = 8.5Hz), 7.80-7.83 (2H, m), 7.93 (2H, d, J = 9.1 Hz), 8.40-8.42 (2H, m). 12579

  4-Amino-1-[4-[6-[(5-fluoro-3- pyridyl)methyl- methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]-4- methylpyrrolidin-2-one ¹H-NMR (CDCl₃) δ:1.46 (3H, s), 2.57 (1H, d, J = 16.9 Hz), 2.68 (1H, d, J = 16.9 Hz), 3.23(3H, s), 3.69 (1H, d, J = 9.7 Hz), 3.80 (1H, d, J = 9.7 Hz), 4.81 (2H,s), 6.79 (1H, d, J = 10.3 Hz), 7.32-7.35 (1H, m), 7.65 (2H, d, J = 8.5Hz), 7.79-7.83 (2H, m), 7.93 (2H, d, J = 9.1 Hz), 8.40-8.42 (2H, m).

Example 126(4S)-4-Amino-1-[4-[6-[(4-chloro-5-fluoro-3-pyridyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

Step 1 4-Chloro-5-fluoropyridine-3-carboxaldehyde

4-Chloro-3-fluoropyridine (1 g) was dissolved in tetrahydrofuran (15ml), and the solution was then cooled to −78° C. Lithiumdiisopropylamide (1.1 M solution in tetrahydrofuran and n-hexane, 7.6ml) was added dropwise thereto, and the mixture was stirred at the sametemperature as above for 5 hours. Then, N,N-dimethylformamide (1 ml) wasadded thereto, and the mixture was further stirred for 30 minutes whilebeing heated to room temperature. Saturated saline was added to thereaction solution, followed by extraction with ethyl acetate. Theextract was washed with water and saturated saline in this order andthen dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure. The obtained residue was purified by silica gelchromatography (n-hexane-ethyl acetate) to obtain the title compound(521 mg).

¹H-NMR (CDCl₃) δ: 8.70 (1H, s), 8.88 (1H, s), 10.47 (1H, s).

Step 2 1-(4-Chloro-5-fluoro-3-pyridyl)-N-methyl-methanamine

The title compound (258 mg) was obtained by the same procedures as instep 1 of Example 117 using the compound (521 mg) obtained in thepreceding step 1 instead of 3-pyridine-carboxaldehyde.

ESI-MS (m/z): 175 (M+H)⁺.

Step 33-Bromo-N-[(4-chloro-5-fluoro-3-pyridyl)methyl]-N-methylimidazo[1,2-b]pyridazin-6-amine

The title compound (140 mg) was obtained by the same procedures as instep 1 of Example 1 using the compound (258 mg) obtained in thepreceding step 2 instead of phenylmethanamine.

¹H-NMR (CDCl₃) δ: 3.30 (3H, s), 4.90 (2H, s), 6.76 (1H, d, J=9.7 Hz),7.54 (1H, s), 7.73 (1H, d, J=9.7 Hz), 8.44 (1H, s), 8.52 (1H, s).

Step 4 tert-ButylN-[(3S)-1-[4-[6-[(4-chloro-5-fluoro-3-pyridyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]-5-oxopyrrolidin-3-yl]carbamate

The title compound (187 mg) was obtained by the same procedures as instep 1 of Example 72 with the compound (140 mg) obtained in thepreceding step 3 as the starting material using the compound (210 mg)obtained in step 3 of Reference Example 65.

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.51 (1H, dd, J=17.2, 4.5 Hz), 3.01 (1H,dd, J=17.5, 7.9 Hz), 3.30 (3H, s), 3.74-3.79 (1H, m), 4.18-4.23 (1H, m),4.44 (1H, br s), 4.83-4.90 (3H, m), 6.79 (1H, d, J=10.3 Hz), 7.62 (2H,d, J=8.5 Hz), 7.81-7.84 (2H, m), 7.90 (2H, d, J=9.1 Hz), 8.25 (1H, s),8.44 (1H, s).

Step 5(4S)-4-Amino-1-[4-[6-[(4-chloro-5-fluoro-3-pyridyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

The title compound (73 mg) was obtained by the same procedures as instep 2 of Example 72 with the compound (185 mg) obtained in thepreceding step 4 as the starting material.

¹H-NMR (DMSO-d₆): 2.22 (1H, dd, J=16.6, 4.5 Hz), 2.73 (1H, dd, J=16.6,7.0 Hz), 3.32 (3H, s), 3.45 (1H, dd, J=9.7, 3.6 Hz), 3.63-3.68 (1H, m),3.96 (1H, dd, J=9.7, 6.0 Hz), 4.93 (2H, s), 7.16 (1H, d, J=9.7 Hz), 7.62(2H, d, J=9.1 Hz), 7.89-7.97 (4H, m), 8.26 (1H, s), 8.64 (1H, s).

Example 127(4S)-4-Amino-1-[5-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]pyrrolidin-2-one

Step 1 tert-ButylN-[(3S)-1-[5-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]-5-oxopyrrolidin-3-yl]carbamate

1,4-Dioxane (15 ml) was added to the compound (1.12 g) obtained in step2 of Reference Example 70, bis(pinacolato)diborane (0.838 g), a[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethaneadduct (0.257 g), and potassium acetate (0.617 g), and the mixture wasstirred at 90° C. for 1 hour and then at 100° C. for 1.5 hours under anitrogen atmosphere.

The reaction solution was brought back to room temperature. The compound(1.06 g) obtained in step 1 of Example 15, tripotassium phosphate (1.33g), a[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethaneadduct (0.257 g), and water (1.5 ml) were added thereto, and the mixturewas heated at 100° C. for 1.5 hours under a nitrogen atmosphere and thenheated to reflux for 1 hour. The reaction solution was diluted withethyl acetate and water to separate the aqueous and organic layers. Theaqueous layer was subjected to extraction with ethyl acetate. Theorganic layers were combined, washed with saturated saline, dried overanhydrous sodium sulfate and then concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography(basic silica gel, n-hexane-ethyl acetate) to obtain the title compound(0.839 g).

¹H-NMR (CDCl₃) δ: 1.47 (9H, br s), 1.69 (3H, d, J=6.0 Hz), 2.64 (1H, dd,J=17.5, 3.6 Hz), 3.08 (1H, dd, J=17.5, 7.9 Hz), 4.08-4.12 (1H, m),4.40-4.48 (2H, m), 4.90 (1H, br s), 5.92 (1H, q, J=6.4 Hz), 6.82 (1H, d,J=9.7 Hz), 6.98 (1H, td, J=8.5, 2.4 Hz), 7.13 (1H, d, J 9.7 Hz), 7.20(1H, d, J=7.9 Hz), 7.33-7.39 (1H, m), 7.83 (1H, s), 7.87 (1H, d, J=9.7Hz), 8.02 (1H, dd, J 8.5, 2.4 Hz), 8.45 (1H, d, J=8.5 Hz), 8.75 (1H, d,J=2.4 Hz).

ESI-MS (m/z): 533 (M+H)⁺.

Step 2(4S)-4-Amino-1-[5-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]pyrrolidin-2-one

The title compound (430 mg) was obtained by the same procedures as instep 2 of Example 79 using the compound (804 mg) obtained in thepreceding step 1.

¹H-NMR (CDCl₃) δ: 1.69 (3H, d, J=6.7 Hz), 2.50 (1H, dd, J=17.0, 4.2 Hz),3.00 (1H, dd, J=17.0, 7.0 Hz), 3.85-3.90 (1H, m), 3.93 (1H, dd, J=11.5,4.2 Hz), 4.35 (1H, dd, J=11.5, 6.0 Hz), 5.93 (1H, q, J=6.7 Hz), 6.81(1H, d, J=9.7 Hz), 6.98 (1H, td, J=8.3, 2.6 Hz), 7.12-7.16 (1H, m), 7.20(1H, d, J=7.9 Hz), 7.36 (1H, td, J=8.0, 5.6 Hz), 7.83 (1H, s), 7.86 (1H,d, J=9.7 Hz), 8.03 (1H, dd, J=9.1, 2.4 Hz), 8.49 (1H, d, J=9.1 Hz), 8.74(1H, d, J=2.4 Hz).

ESI-MS (m/z): 433 (M+H)⁺.

The following compounds were obtained by the same procedures as inExample 127.

TABLE 25-1 Reference Example Example No. No. Structure and nameInstrumental data 128 70

  (4S)-4-Amino-1-[5-[6-[(3- fluorophenyl)methyl-methylamino]imidazo[1,2- b]pyridazin-3-yl]-2- pyridyl]pyrrolidin-2-one¹H-NMR (CDCl₃) δ: 2.47 (1H, dd, J = 16.9, 4.2 Hz), 2.97 (1H, dd, J =17.2, 7.0 Hz), 3.23 (3H, s), 3.82-3.96 (2H, m), 4.31 (1H, dd, J = 11.5,6.0 Hz), 4.74 (2H, s), 6.78 (1H, d, J = 10.3 Hz), 6.91-7.09 (3H, m),7.29-7.36 (1H, m), 7.77 (1H, d, J = 10.3 Hz), 7.85 (1H, s), 8.28-8.37(1H, m), 8.44 (1H, d, J = 9.7 Hz), 8.91-8.99 (1H, m). 129 70

  (4S)-4-Amino-1-[5-[6-[(2,5- difluorophenyl)methyl-methylamino]imidazo[1,2- b]pyridazin-3-yl]-2- pyridyl]pyrrolidin-2-one¹H-NMR (CDCl₃) δ: 2.47 (1H, dd, J = 16.9, 4.2 Hz), 2.97 (1H, dd, J =16.9, 7.3 Hz), 3.25 (3H, s), 3.82-3.92 (2H, m), 4.31 (1H, dd, J = 11.5,6.0 Hz), 4.76 (2H, s), 6.79 (1H, d, J = 10.3 Hz), 6.87-6.97 (2H, m),7.06-7.11 (1H, m), 7.79 (1H, d, J = 10.3 Hz), 7.85 (1H, s), 8.30-8.33(1H, m), 8.44 (1H, d, J = 9.7 Hz), 8.92-8.94 (1H, m). 130 76

  2-[(4S)-4-Amino-2- oxopyrrolidin-1-yl]-5-[6-[(5-fluoro-3-pyridyl)methyl]- methylamino]imidazo[1,2-b]pyridazin-3-yl]benzonitrile ¹H-NMR (CDCl₃) δ: 2.42 (1H, dd, J = 17.2,4.5 Hz), 2.92 (1H, dd, J = 16.9, 7.3 Hz), 3.27 (3H, s), 3.65 (1H, dd, J= 9.7, 4.2 Hz), 3.90-3.96 (1H, m), 4.19 (1H, dd, J = 9.7, 6.0 Hz), 4.83(2H, s), 6.86 (1H, d, J = 10.3 Hz), 7.31-78.34 (1H, m), 7.49 (1H, d, J =8.5 Hz), 7.84 (1H, d, J = 10.3 Hz), 7.90 (1H, s), 8.11 (1H, dd, J = 8.8,2.1 Hz), 8.39-8.42 (2H, m), 8.47- 8.48 (1H, m).

TABLE 25-2 131 76

  2-[(4S)-4-Amino-2- oxopyrrolidin-1-yl]-5-[6-[(3- fluorophenyl)methyl-methylamino]imidazo[1,2- b]pyridazin-3-yl]benzonitrile ¹H-NMR (CDCl₃) δ:2.42 (1H, dd, J = 16.9, 4.8 Hz), 2.93 (1H, dd, J = 16.9, 7.3 Hz), 3.26(3H, s), 3.65 (1H, dd, J = 9.7, 3.6 Hz), 3.90-3.96 (1H, m), 4.20 (1H,dd, J = 9.7, 6.0 Hz), 4.77 (2H, s), 6.82 (1H, d, J = 9.7 Hz), 6.93-6.99(2H, m), 7.05 (1H, d, J = 7.9 Hz), 7.31-7.37 (1H, m), 7.49 (1H, d, J =8.5 Hz), 7.79 (1H, d, J = 9.7 Hz), 7.89 (1H, s), 8.18 (1H, dd, J = 8.5,2.4 Hz), 8.54-8.55 (1H, m). 132 70

  (4S)-4-Amino-1-[5-[6-[(2,3- difluorophenyl)methyl-methylamino]imidazo[1,2- b]pyridazin-3-yl]-2- pyridyl]pyrrolidin-2-one¹H-NMR (CDCl₃) δ: 2.47 (1H, dd, J = 16.9, 4.2 Hz), 2.97 (1H, dd, J =17.2, 7.0 Hz), 3.23 (3H, s), 3.82-3.92 (2H, m), 4.32 (1H, dd, J = 11.2,6.3 Hz), 4.81 (2H, s), 6.80 (1H, d, J = 9.7 Hz), 6.93- 7.04 (2H, m),7.06-7.14 (1H, m), 7.78 (1H, d, J = 9.7 Hz), 7.84 (1H, s), 8.34 (1H, dd,J = 9.1, 2.4 Hz), 8.47 (1H, d, J = 9.1 Hz), 8.94 (1H, d, J = 1.8 Hz).

Example 133(4S)-4-Amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-onehydrochloride

The compound (15.65 g) obtained in step 2 of Example 79 was dissolved ina mixed solvent of ethanol (400 ml) and methanol (10 ml). To thesolution, a solution of 1 N hydrochloric acid in ethanol (74.4 ml) wasadded, and the mixture was stirred at room temperature for 10 minutes.Then, the solvent was distilled off under reduced pressure. Diethylether was added to the residue, and the solid was collected byfiltration to obtain the title compound (17.16 g).

¹H-NMR (DMSO-d₆) δ: 1.68 (3H, d, J=6.7 Hz), 2.67 (1H, dd, J=17.5, 3.0Hz), 3.08 (1H, dd, J=17.5, 8.5 Hz), 3.94 (1H, dd, J=11.5, 2.4 Hz),4.07-4.14 (1H, m), 4.30 (1H, dd, J=11.5, 7.0 Hz), 6.07 (1H, q, J=6.7Hz), 7.12 (1H, td, J=8.3, 2.0 Hz), 7.31 (1H, d, J=9.7 Hz), 7.33-7.37(2H, m), 7.43 (1H, td, J=8.3, 6.0 Hz), 7.78-7.82 (2H, m), 7.93-7.97 (2H,m), 8.27 (1H, d, J=9.7 Hz), 8.34 (1H, s), 8.58-8.68 (3H, m).

ESI-MS (m/z): 432 (M+H)⁺.

Example 134(4S)-4-Amino-1-[4-[6-[(1-(2,5-difluoro-3-pyridyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-onehydrochloride

The compound (567 mg) obtained in step 3 of Example 106 was dissolved indichloromethane. To the solution, a solution of 1 N hydrochloric acid inethanol (2.77 ml) was added. The solvent was distilled off under reducedpressure. Diethyl ether was added to the residue, and the solid wascollected by filtration to obtain the title compound (643 mg).

¹H-NMR (DMSO-d₆) δ: 1.72 (3H, d, J=6.7 Hz), 2.64 (1H, dd, J=17.5, 3.0Hz), 3.08 (1H, dd, J=17.5, 8.5 Hz), 3.91 (1H, dd, J=10.9, 2.4 Hz),4.06-4.13 (1H, m), 4.30 (1H, dd, J=10.9, 7.0 Hz), 6.16 (1H, q, J=6.7Hz), 7.29 (1H, d, J=9.7 Hz), 7.75-7.79 (2H, m), 7.89-7.92 (2H, m), 8.08(1H, td, J=7.6, 3.0 Hz), 8.20-8.22 (1H, m), 8.28 (1H, d, J=9.7 Hz), 8.32(1H, s), 8.52 (3H, br s). ESI-MS (m/z): 451 (M+H)⁺.

Example 135(4S)-4-(Dimethylamino)-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

Step 1(4S)-4-(Dimethylamino)-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-one

The compound (127 mg) obtained in Example 131 was suspended indichloromethane (5 ml). To the suspension, a 35% aqueous formaldehydesolution (47 μl), triethylamine (82 μl), and sodiumtriacetoxyborohydride (149 mg) were added, and the mixture was stirredat room temperature for 1.5 hours. Dichloromethane and water were addedthereto to separate the aqueous and organic layers. The aqueous layerwas subjected to extraction with dichloromethane. The organic layerswere combined, dried over anhydrous sodium sulfate and then concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (basic silica gel, ethyl acetate). After additionof n-hexane, the solid was collected by filtration to obtain the titlecompound (86 mg).

¹H-NMR (CDCl₃) δ: 1.69 (3H, d, J=6.6 Hz), 2.33 (6H, s), 2.67 (1H, dd,J=16.8, 8.6 Hz), 2.79 (1H, dd, J=16.8, 7.8 Hz), 3.12-3.19 (1H, m), 3.81(1H, dd, J=9.5, 6.8 Hz), 3.99 (1H, dd, J=9.5, 7.4 Hz), 5.93 (1H, q, J6.5 Hz), 6.79 (1H, d, J=9.4 Hz), 6.96-7.01 (1H, m), 7.15 (1H, dt, J=9.8,2.2 Hz), 7.22 (1H, d, J=8.0 Hz), 7.36 (1H, td, J=8.0, 5.9 Hz), 7.68-7.75(4H, m), 7.81 (1H, s), 7.85 (1H, d, J=9.4 Hz).

ESI-MS (m/z): 460 (M+H)⁺.

Example 136N-[(1R)-1-(3-Fluorophenyl)ethyl]-3-[4-[[(2S)-pyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2-b]pyridazin-6-aminemonomaleate

ToN-[(1R)-1-(3-fluorophenyl)ethyl]-3-[4-[[(2S)-pyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2-b]pyridazin-6-amine(105 mg) obtained in Example 24, water (1.8 ml) and a 1 mol/l aqueousmaleic acid solution (242 μl) were added at room temperature. Then, themixture was stirred at 40° C. for 20 hours and further stirred at roomtemperature for 0.5 hours. Then, the deposited solid was collected byfiltration to obtain the title compound (112 mg).

¹H-NMR (DMSO-d₆) δ: 1.49 (3H, d, J=6.7 Hz), 1.71-1.81 (1H, m), 1.87-2.04(2H, m), 2.10-2.21 (1H, m), 3.19-3.28 (2H, m), 3.89-3.98 (1H, m), 4.12(1H, t, J=9.7 Hz), 4.30 (1H, dd, J=10.6, 3.3 Hz), 4.80-4.89 (1H, m),6.02 (2H, s), 6.78 (1H, d, J=9.7 Hz), 6.98 (2H, d, J=9.7 Hz), 7.04 (1H,td, J=8.5, 2.4 Hz), 7.22-7.29 (2H, m), 7.36-7.43 (1H, m), 7.66 (1H, d,J=6.0 Hz), 7.75-7.84 (4H, m), 8.84 (1H, br s).

Anal. Calcd for C₂₅H₂₆FN₅O.C₄H₄O₄: C, 63.61; H, 5.52; F, 3.47; N, 12.79.Found: C, 62.26; H, 5.45; F, 4.25; N, 12.54.

Example 137N-[(1R)-1-(3-Fluorophenyl)ethyl]-3-[4-[[(2S)-pyrrolidin-2-yl]methoxy]phenyl]imidazo[1,2-b]pyridazin-6-aminemonoadipate monohydrate

To the compound (104 mg) obtained in Example 24, adipic acid (38 mg) andwater (2 ml) were added at room temperature. Then, the mixture wasstirred at 40° C. for 20 hours and further stirred at room temperaturefor 0.5 hours. Then, the deposited solid was collected by filtration toobtain the title compound (125 mg).

¹H-NMR (DMSO-d₆) δ: 1.46-1.55 (5H, m), 1.48 (3H, d, J=7.3 Hz), 1.63-1.81(2H, m), 1.86-1.95 (1H, m), 2.16-2.21 (4H, m), 2.82-2.93 (2H, m),3.43-3.51 (1H, m), 3.89 (2H, d, J=6.7 Hz), 4.80-4.88 (1H, m), 6.77 (1H,d, J=9.7 Hz), 6.92 (2H, d, J=8.5 Hz), 7.03 (1H, td, J=8.3, 2.4 Hz),7.22-7.29 (2H, m), 7.36-7.43 (1H, m), 7.63 (1H, d, J=6.0 Hz), 7.71-7.77(4H, m).

Anal. Calcd for C₂₅H₂₆FN₅O.C₆H₁₀O₄.H₂O: C, 62.51; H, 6.43; F, 5.32; N,11.76. Found: C, 61.01; H, 6.16; F, 5.32; N, 11.45.

Example 138(4S)-4-Amino-1-[4-[6-[(3-fluorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-onemonobenzenesulfonate

To the compound (102 mg) obtained in step 2 of Example 81, acetone (1.8ml), water (146 μl), and a 4 mol/l aqueous benzenesulfonic acid solution(59 μl) were added at room temperature. Then, the mixture was stirred atroom temperature for 3 hours. Then, the deposited solid was collected byfiltration to obtain the title compound (121 mg).

¹H-NMR (DMSO-d₆) δ: 2.54 (1H, dd, J=17.5, 3.0 Hz), 3.06 (1H, dd, J=17.5,8.5 Hz), 3.24 (3H, s), 3.79 (1H, dd, J=11.2, 2.1 Hz), 4.04-4.10 (1H, m),4.26 (1H, dd, J=10.9, 7.3 Hz), 4.84 (2H, s), 7.05-7.15 (4H, m),7.27-7.41 (4H, m), 7.58-7.61 (2H, m), 7.70 (2H, d, J=9.1 Hz), 7.92 (1H,d, J=9.7 Hz), 7.97 (1H, s), 8.11 (3H, br s), 8.12 (2H, d, J=9.1 Hz).

Anal. Calcd for C₂₄H₂₃FN₆O.C₆H₆O₃S: C, 61.21; H, 4.97; F, 3.23; N,14.28, S; 5.45. Found: C, 60.84; H, 5.04; F, 3.40; N, 14.13, S; 5.40.

Example 139(4S)-4-Amino-1-[4-[6-[(3-fluorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-onemonoadipate

To the compound (105 mg) obtained in step 2 of Example 81, adipic acid(39 mg) and acetone (1 ml) were added at room temperature. The mixturewas stirred at 40° C. for 20 hours. Then, ethyl acetate (3.2 ml) wasadded thereto, and the mixture was further stirred at room temperaturefor 0.5 hours. The deposited solid was collected by filtration to obtainthe title compound (124 mg).

¹H-NMR (DMSO-d₆) δ: 1.46-1.53 (4H, m), 2.17-2.26 (5H, m), 2.75 (1H, dd,J=16.6, 7.0 Hz), 3.24 (3H, s), 3.48 (1H, dd, J=9.7, 3.6 Hz), 3.63-3.70(1H, m), 3.99 (1H, dd, J=9.7, 6.7 Hz), 4.83 (2H, s), 7.05-7.15 (4H, m),7.35-7.42 (1H, m), 7.69 (2H, d, J=9.1 Hz), 7.90 (1H, d, J=9.7 Hz), 7.94(1H, s), 8.08 (2H, d, J=9.1 Hz).

Anal. Calcd for C₂₄H₂₃FN₆O.C₆H₁₀O₄: C, 62.49; H, 5.77; F, 3.29; N,14.57. Found: C, 62.08; H, 5.70; F, 3.76; N, 14.32.

Example 140(4S)-4-Amino-1-[4-[6-[(3-fluorophenyl)methyl-methylamino]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-onemonocamphorate monohydrate

To the compound (100 mg) obtained in step 2 of Example 81, camphoricacid (39 mg), acetone (1.8 ml), and water (200 μl) were added at roomtemperature. The mixture was stirred at 40° C. for 20 hours and furtherstirred at room temperature for 0.5 hours. The deposited solid wascollected by filtration to obtain the title compound (93 mg).

¹H-NMR (DMSO-d₆) δ: 0.77 (3H, s), 1.12 (3H, s), 1.18 (3H, s), 1.33-1.40(1H, m), 1.66-1.77 (1H, m), 1.93-2.02 (1H, m), 2.24 (1H, dd, J=16.3, 4.2Hz), 2.29-2.39 (1H, m), 2.69-2.79 (2H, m), 3.24 (3H, s), 3.49 (1H, dd,J=9.7, 3.6 Hz), 3.64-3.70 (1H, m), 4.00 (1H, dd, J=9.7, 6.0 Hz), 4.83(2H, s), 7.05-7.15 (4H, m), 7.35-7.42 (1H, m), 7.69 (2H, d, J=8.5 Hz),7.90 (1H, d, J=9.7 Hz), 7.95 (1H, s), 8.07 (2H, d, J=8.5 Hz).

Anal. Calcd for C₂₄H₂₃FN₆O.C₁₀H₁₆O₄.H₂O: C, 62.95; H, 6.37; F, 2.93; N,12.95.

Found: C, 62.44; H, 6.25; F, 3.37; N, 13.01.

Example 141(4S)-4-Amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-onemonobenzenesulfonate monohydrate

To the compound (101 mg) obtained in step 2 of Example 79, acetone (202μl), water (574 μl), and a 1 mol/l aqueous benzenesulfonic acid solution(233 μl) were added at room temperature. The mixture was stirred at 40°C. for 20 hours and further stirred at room temperature for 0.5 hours.The deposited solid was collected by filtration to obtain the titlecompound (131 mg).

¹H-NMR (DMSO-d₆) δ: 1.67 (3H, d, J=6.7 Hz), 2.57 (1H, dd, J=17.8, 2.7Hz), 3.09 (1H, dd, J=18.1, 8.5 Hz), 3.83 (1H, dd, J=11.2, 2.1 Hz),4.07-4.14 (1H, m), 4.30 (1H, dd, J=11.2, 7.0 Hz), 6.05 (1H, q, J=6.4Hz), 7.03 (1H, d, J=9.7 Hz), 7.10 (1H, td, J=8.5, 1.8 Hz), 7.29-7.44(6H, m), 7.58-7.61 (2H, m), 7.77 (2H, d, J=9.4 Hz), 7.96 (2H, d, J=9.1Hz), 8.07 (1H, s), 8.11 (1H, d, J=10.9 Hz), 8.16 (3H, br s).

Anal. Calcd for C₂₄H₂₂FN₅O₂.C₆H₇O₃S.H₂O: C, 59.30; H, 4.98; F, 3.13; N,11.53; S, 5.28. Found: C, 59.10; H, 5.01; F, 3.25; N, 11.37; S, 5.15.

Example 142(4S)-4-Amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-onemonoadipate

To the compound (101 mg) obtained in step 2 of Example 79, adipic acid(37 mg) and 1,2-methoxyethane (1 ml) were added at room temperature. Themixture was stirred at 40° C. for 3 hours. Then, ethyl acetate (1 ml)was added thereto, and the mixture was stirred at room temperature for 3hours. The deposited solid was collected by filtration to obtain thetitle compound (126 mg).

¹H-NMR (DMSO-d₆) δ: 1.46-1.52 (4H, m), 1.66 (3H, d, J=6.7 Hz), 2.17-2.22(4H, m), 2.26 (1H, dd, J=16.9, 3.0 Hz), 2.77 (1H, dd, J=16.6, 7.0 Hz),3.53 (1H, dd, J=9.7, 3.6 Hz), 3.66-3.73 (1H, m), 4.03 (1H, dd, J=9.7,6.0 Hz), 6.04 (1H, q, J=6.4 Hz), 7.02 (1H, d, J=9.7 Hz), 7.11 (1H, td,J=8.5, 3.0 Hz), 7.31-7.36 (2H, m), 7.39-7.46 (1H, m), 7.75 (2H, d, J=9.1Hz), 7.90 (2H, d, J=9.1 Hz), 8.03 (1H, s), 8.09 (1H, d, J=9.7 Hz).

Anal. Calcd for C₂₄H₂₂FN₅O₂.C₆H₁₀O₄: C, 62.38; H, 5.58; F, 3.29; N,12.12. Found: C, 62.25; H, 5.57; F, 3.38; N, 12.05.

Example 143(4S)-4-Amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-onemonolactate monohydrate

To the compound (103 mg) obtained in step 2 of Example 79, acetone (924μl), water (43 μl), and a 4 mol/l aqueous lactic acid solution (59 μl)were added at room temperature. The mixture was stirred at 40° C. for 20hours and further stirred at room temperature for 0.5 hours. Thedeposited solid was collected by filtration to obtain the title compound(95 mg).

¹H-NMR (DMSO-d₆) δ: 1.19 (3H, d, J=6.7 Hz), 1.67 (3H, d, J=6.7 Hz), 2.34(1H, dd, J=16.9, 4.2 Hz), 2.84 (1H, dd, J=16.9, 7.3 Hz), 3.61 (1H, dd,J=10.0, 3.3 Hz), 3.76-3.82 (1H, m), 3.91 (1H, q, J=6.9 Hz), 4.09 (1H,dd, J=10.0, 6.3 Hz), 6.04 (1H, q, J=6.4 Hz), 7.02 (1H, d, J=9.7 Hz),7.10 (1H, td, J=8.3, 2.2 Hz), 7.31-7.36 (2H, m), 7.39-7.45 (1H, m), 7.75(2H, d, J=9.1 Hz), 7.91 (2H, d, J=9.1 Hz), 8.04 (1H, s), 8.10 (1H, d, J9.7 Hz).

Anal. Calcd for C₂₄H₂₂FN₅O₂.C₃H₆O₃.H₂O: C, 60.10; H, 5.60; F, 3.52; N,12.98.

Found: C, 59.71; H, 5.57; F, 3.81; N, 12.85.

Example 144(4S)-4-Amino-1-[4-[6-[(1R)-1-(3-fluorophenyl)ethoxy]imidazo[1,2-b]pyridazin-3-yl]phenyl]pyrrolidin-2-onemonobenzoate monohydrate

To the compound (101.01 mg) obtained in step 2 of Example 79, benzoicacid (31 mg), acetone (916 μl), and water (102 μl) were added at roomtemperature. The mixture was stirred at 40° C. for 24 hours and furtherstirred at room temperature for 0.5 hours. The deposited solid wascollected by filtration to obtain the title compound (119 mg).

¹H-NMR (DMSO-d₆) δ: 1.66 (3H, d, J=6.7 Hz), 2.30 (1H, dd, J=16.6, 3.9Hz), 2.81 (1H, dd, J=16.9, 7.3 Hz), 3.57 (1H, dd, J=9.7, 3.6 Hz),3.71-3.77 (1H, m), 4.06 (1H, dd, J=9.7, 6.0 Hz), 6.04 (1H, q, J=6.4 Hz),7.02 (1H, d, J=9.7 Hz), 7.10 (1H, td, J=8.5, 2.3 Hz), 7.31-7.36 (2H, m),7.39-7.45 (1H, m), 7.47 (2H, t, J=7.9 Hz), 7.58 (1H, tt, J=7.3, 1.6 Hz),7.75 (2H, d, J=9.1 Hz), 7.91 (2H, d, J=9.1 Hz), 7.93 (2H, d, J=8.5 Hz),8.04 (1H, s), 8.09 (1H, d, J=9.7 Hz).

Anal. Calcd for C₂₄H₂₂FN₅O₂.C₇H₆O₂.H₂O: C, 65.14; H, 5.29; F, 3.32; N,12.25.

Found: C, 64.91; H, 5.29; F, 3.62; N, 12.16.

Example 1453-[4-[(2R)-2-Aminopropoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-aminedimethanesulfonate

To the compound (503 mg) obtained in step 3 of Example 21,methanesulfonic acid (169 μl) and 1-propanol (5 ml) were added at roomtemperature. The mixture was stirred at 40° C. for 24 hours and furtherstirred at room temperature for 0.5 hours. The deposited solid wascollected by filtration to obtain the title compound (642 mg).

¹H-NMR (DMSO-d6) δ: 1.32 (3H, d, J=6.7 Hz), 1.51 (3H, d, J=6.7 Hz), 2.32(6H, s), 3.63-3.74 (1H, m), 4.05 (1H, dd, J=10.3, 7.3 Hz), 4.21 (1H, dd,J=10.0, 3.9 Hz), 4.81-4.89 (1H, m), 7.04-7.10 (3H, m), 7.22-7.29 (3H,m), 7.38-7.44 (1H, m), 7.78 (2H, d, J=9.1 Hz), 8.03 (3H, br s), 8.06(1H, d, J=10.3 Hz), 8.29 (1H, s), 8.33 (1H, d, J=6.0 Hz).

Anal. Calcd for C₂₃H₂₄FN₅O.2CH₄O₃S: C, 50.24; H, 5.40; N, 11.72. Found:C, 49.68; H, 5.30; N, 11.55.

Example 1463-[4-[(2R)-2-Aminopropoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-aminemonoadipate

To the compound (500 mg) obtained in step 3 of Example 21, adipic acid(181 mg) and 1-propanol (5 ml) were added at room temperature. Themixture was stirred at 40° C. for 24 hours and further stirred at roomtemperature for 0.5 hours. The deposited solid was collected byfiltration to obtain the title compound (622 mg).

¹H-NMR (DMSO-d₆) δ: 1.11 (3H, d, J=6.0 Hz), 1.46-1.51 (4H, m), 1.48 (3H,d, J=7.3 Hz), 2.15-2.21 (4H, m), 3.18-3.27 (1H, m), 3.77-3.86 (2H, m),4.80-4.88 (1H, m), 6.77 (1H, d, J=9.7 Hz), 6.93 (2H, d, J=9.1 Hz), 7.03(1H, td, J=8.5, 2.4 Hz), 7.22-7.29 (2H, m), 7.36-7.43 (1H, m), 7.61 (1H,d, J=6.0 Hz), 7.70-7.77 (4H, m).

Anal. Calcd for C₂₃H₂₄FN₅O.C₆H₁₀O₄: C, 63.14; H, 6.21; N, 12.70. Found:C, 62.97; H, 6.29; N, 12.59.

Test Example 1 ROS1 Kinase Inhibitory Activity Evaluation

A hundred mM HEPES (pH 7.4), 0.003% Brij-35, 0.004% Tween-20, 1 mM DTT,ROS1 (Carna Biosciences #08-163, final concentration: 25 pg/μL), andMgCl (final concentration: 10 mM) were mixed to prepare a ROS1 kinasesolution.

Next, a substrate reaction solution was prepared. The composition is asfollows: 100 mM HEPES (pH 7.4), 0.003% Brij-35, 0.004% Tween-20, 1 mMDTT, FL-Peptide 22 (Caliper Life Sciences #760366, final concentration:1.5 μM), and ATP (final concentration: Km=55 μM or 1 mM). A reactionstop solution is prepared. The composition is as follows: 100 mM HEPES(pH 7.4), 0.015% Brij-35, 40 mM EDTA, and 0.1% Coating Reagent 3(Caliper Life Sciences #760050).

The ROS1 kinase solution was added at a concentration of 19 μL/well to a96-well plate. Each compound for evaluation dissolved in DMSO to achieveeach final concentration was added to the plate, mixed using a platemixer, and then preincubated at room temperature for 20 minutes. Thesubstrate reaction solution was further added thereto at a concentrationof 5 μL/well to cause enzymatic reaction (28° C. for 90 minutes underthe condition of ATP=Km or 45 minutes under the condition of 1 mM ATP).Then, the reaction stop solution was added thereto at a concentration of40 μL/well. Substrate phosphorylation intensity was measured using EZReader II (Caliper Life Sciences). IC₅₀ values were calculated by curvefitting using Microsoft Excel 2010 on the basis of data obtained fromthree separate measurements.

The compounds of Examples 16, 18, 21 to 24, 26, 28 to 30, 32 to 50, 52to 56, 59, 62 to 63, 69 to 70, 72, 76 to 77, 79 to 82, 88, 90, 92 to 93,104, 106 to 107, 114, 120, 127 to 128, and 133 exhibited ROS1 kinaseinhibitory activity at IC₅₀ of lower than 1 nM. The compounds ofExamples 1 to 15, 17, 19 to 20, 25, 27, 31, 51, 57 to 58, 60 to 61, 64to 68, 71, 73 to 75, 78, 83 to 87, 91, 94 to 103, 108, 110 to 113, 117to 119, 121 to 122, 124 to 126, 129, 131 to 132, and 134 to 135exhibited ROS1 kinase inhibitory activity at IC₅₀ of 1 nM or higher andlower than 10 nM. The compounds of Examples 89, 105, 109, 115 to 116,123, and 130 exhibited ROS1 kinase inhibitory activity at IC₅₀ of 10 nMor higher and lower than 60 nM. This suggested that the compounds of thepresent invention can suppress the growth of cells with the activatedROS1 pathway by inhibiting the ROS1 pathway.

Test Example 2 ROS1 Autophosphorylation Inhibitory Activity Evaluation

Fifty mM HEPES (pH 7.5), 10 mM MgCl2, 0.01% Brij-58, and 2.5 mM DTT weremixed to prepare an enzymatic reaction solution. Each compound forevaluation dissolved in DMSO to achieve each final concentration wasadded to the enzymatic reaction solution containing 200 nM inactiveROS1, and the mixture was added at a concentration of 2.5 μL/well to a384-well plate (small volume black, Grainer #784900). ATP (finalconcentration: 1 mM) was further added thereto at a concentration of 2.5μL/well. The resulting plate was left standing at 25° C. for 1.5 hoursto cause enzymatic reaction. After the completion of enzymatic reaction,ADP-Glo Reagent-1 (Promega, V9103) was added thereto at a concentrationof 2.5 μL/well, and the plate was left standing at room temperature for60 minutes. Then, ADP-Glo Reagent-2 (Promega) was added thereto at aconcentration of 5 μL/well, and the plate was left standing at roomtemperature for 60 minutes. The amount of ADP generated by theautophosphorylation of ROS1 was measured using EnVision (PerkinElmerJapan). The amount of ADP generated in four separate measurements wasdefined as the autophosphorylation intensity of ROS1. IC₅₀ values werecalculated by curve fitting using GraphPad Prism version 4 (GraphPadsoftware).

The compounds of Examples 19, 21 to 36, 38 to 56, 58 to 61, 63, 65 to73, 76, 78 to 82, 85 to 86, 88, 90 to 93, 98, 100, 102, 104, 106 to 107,110, 112 to 114, 118 to 120, 124, 127 to 128, 131, and 133 to 134exhibited ROS1 autophosphorylation inhibitory activity at IC₅₀ of lowerthan 20 nM. The compounds of Examples 1 to 3, 5 to 6, 8, 10 to 12, 14 to15, 17 to 18, 20, 37, 57, 62, 75, 77, 83 to 84, 87, 89, 94 to 97, 99,101, 103, 105, 108, 111, 117, 121 to 122, 125 to 126, 129 to 130, 132,and 135 exhibited ROS1 autophosphorylation inhibitory activity at IC₅₀of 20 nM or higher and lower than 100 nM. The compounds of Examples 4,7, 9, 13, 64, 74, 109, 115 to 116, and 123 exhibited ROS1autophosphorylation inhibitory activity at IC₅₀ of 100 nM or higher andlower than 150 nM. This suggested that the compounds of the presentinvention can suppress the growth of cells with the activated ROS1pathway by inhibiting the ROS1 pathway.

Test Example 3 NTRK Kinase Enzyme Inhibitory Activity Evaluation

NTRK1, NTRK2, and NTRK3 kinase solutions were each prepared. Thecomposition is as follows: 100 mM HEPES (pH 7.4), 0.003% Brij-35, 0.004%Tween-20, 1 mM DTT, NTRK (for NTRK1, Carna Biosciences #08-186, finalconcentration: 140 ng/mL; for NTRK2, Carna Biosciences #08-187, finalconcentration: 100 ng/mL; and for NTRK3, Carna Biosciences #08-197,final concentration: 50 ng/mL), and MgCl (final concentration: 10 mM).

Next, a substrate reaction solution was prepared. The composition is asfollows: 100 mM HEPES (pH 7.4), 0.003% Brij-35, 0.004% Tween-20, 1 mMDTT, FL-Peptide 27 (Caliper Life Sciences #760424, final concentration:1.5 μM), and ATP (for NTRK1, final concentration: Km=33 μM; for NTRK2,final concentration: Km=63 μM; and for NTRK3, final concentration: Km=32μM).

Subsequently, a reaction stop solution was prepared. The composition isas follows: 100 mM HEPES (pH 7.4), 0.015% Brij-35, 40 mM EDTA, and 0.1%Coating Reagent 3 (Caliper Life Sciences #760050).

The NTRK1, NTRK2, and NTRK3 kinase solutions were each added at aconcentration of 19 μL/well to a 96-well plate. Each compound forevaluation dissolved in DMSO to achieve each final concentration wasadded to the plate, mixed using a plate mixer, and then preincubated atroom temperature for 20 minutes. The substrate reaction solution wasfurther added thereto at a concentration of 5 μL/well to cause enzymaticreaction (28° C. for 90 minutes under the condition of ATP=Km or 45minutes under the condition of 1 mM ATP). Then, the reaction stopsolution was added thereto at a concentration of 40 μL/well. Substratephosphorylation intensity was measured using EZ Reader II (Caliper LifeSciences). IC₅₀ values were calculated by curve fitting using MicrosoftExcel 2010 on the basis of data obtained from three separatemeasurements.

The compounds of Examples 21, 24, 29, 30, 41, 79, 81, 85, and 90exhibited NTRK1 inhibitory activity at IC₅₀ of lower than 5 nM. Thecompound of Example 127 exhibited NTRK1 inhibitory activity at IC₅₀ of10 nM or higher and lower than 15 nM. The compounds of Examples 21, 24,29, 30, 41, 79, 81, 85, and 90 exhibited NTRK2 inhibitory activity atIC₅₀ of lower than 10 nM. The compound of Example 127 exhibited NTRK2inhibitory activity at IC₅₀ of 20 nM or higher and lower than 25 nM. Thecompounds of Examples 21, 24, 29, 30, 41, 79, 81, 85, and 90 exhibitedNTRK3 inhibitory activity at IC₅₀ of lower than 5 nM. The compound ofExample 127 exhibited NTRK3 inhibitory activity at IC₅₀ of 5 nM orhigher and lower than 10 nM. This suggested that the compounds of thepresent invention can suppress the growth of cells with activated NTRKby inhibiting NTRK.

Test Example 4 HCC78 Cell Growth Assay

Each compound of the present invention was assayed for its cell growthinhibitory effect using HCC78 cells having ROS1 fusion gene.

HCC78 cells (ATCC) were suspended in RPMI 1640 (Invitrogen, Cat No11875-093) containing 2% FBS (HyClone, Cat No ANC18297) (hereinafter,referred to as a medium) to adjust their concentration to 3×10⁴cells/mL. The suspension was dispensed at a concentration of 100 μL/wellto a 96-well culture plate for cell culture (SUMITOMO BAKELITE, Cat NoMS-0096S) (hereinafter, referred to as an assay plate). A mediumcontaining each compound for evaluation at a final concentration of 0,0.15, 0.61, 2.4, 10, 39, 156, 625, or 2,500 nM was dispensed at aconcentration of 25 μL/well to the assay plate. In this context, thefinal concentration of DMSO was set to 0.4%. Then, the cells werecultured for 72 hours in a CO₂ incubator.

CellTiter-Glo Luminescent Cell Viability Assay reagent (Promega, Cat NoG7571) was dispensed at a concentration of 100 μL/well to the assayplate. The contents in each well were reacted at room temperature for 10minutes while stirred using a plate mixer. A 100 μL aliquot of eachreaction solution was dispensed to each well of a 96-well assay plate,black (CORNING, Cat No 3650). The luminescence intensity of each wellwas measured using EnVision. The luminescence intensity of each wellobtained in four separate measurements was defined as the number ofcells. IC₅₀ values were calculated by curve fitting using GraphPad Prismversion 4.

The compounds of Examples 21, 26, 29 to 30, 35, 38, 40 to 49, 53 to 56,59, 63, 69, 71 to 72, 79, 81, 88, 90, 92 to 93, 97, 106 to 107, 113, 118to 120, 124 to 125, and 133 to 134 exhibited a growth inhibitory effecton HCC78 cells having ROS1 fusion gene at IC₅₀ of lower than 20 nM. Thecompounds of Examples 1, 3, 5 to 8, 16, 18, 22, 24 to 25, 28, 31 to 33,37, 39, 50 to 52, 57 to 58, 60 to 62, 65 to 68, 70, 73, 76 to 78, 80, 82to 87, 91, 98 to 100, 103 to 104, 108 to 112, 114, 117, 121 to 123, 126to 129, and 131 to 132 exhibited a growth inhibitory effect on HCC78cells having ROS1 fusion gene at IC₅₀ of 20 nM or higher and lower than100 nM. The compounds of Examples 2, 4, 9 to 15, 17, 19 to 20, 23, 27,34, 36, 64, 74 to 75, 89, 94 to 96, 101 to 102, 105, 115 to 116, 130,and 135 exhibited a growth inhibitory effect on HCC78 cells having ROS1fusion gene at IC₅₀ of 100 nM or higher and lower than 600 nM. Thissuggested that the compounds of the present invention are effective fora tumor having ROS1 fusion gene.

INDUSTRIAL APPLICABILITY

The compound represented by the general formula (I) of the presentinvention or a pharmacologically acceptable salt thereof has anexcellent ROS1 kinase inhibitory effect and NTRK kinase enzymeinhibitory effect and as such, is useful as a therapeutic drug for atumor with the activated ROS1 pathway and tumor with the activated NTRKpathway.

The invention claimed is:
 1. A compound represented by the general formula (I) or a pharmacologically acceptable salt thereof:

wherein R¹ represents a hydrogen atom, a C₁-C₆ alkyl group, a fluoro-C₁-C₆ alkyl group, or a hydroxy-C₁-C₆ alkyl group; Q represents an oxygen atom or R^(a)N, wherein R^(a) represents a hydrogen atom or a C₁-C₆ alkyl group; G is represented by the following formula (IV):

 wherein U represents a nitrogen atom or CH; R⁷ represents a hydrogen atom or a C1-C6 alkyl group; and R⁸ represents a hydrogen atom, a C1-C6 alkyl group, or a halogen atom, or is represented by G^(a) to G^(e):

T represents a nitrogen atom or CR^(b), wherein R^(b) represents a hydrogen atom, a halogen atom, a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, or a cyano group; Y¹ and Y² each independently represents a hydrogen atom, a halogen atom, a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, or a cyano group;

Y³ represents a hydrogen atom; and Y⁴ is represented by —O-M², formula (V), Y^(a), or Y^(b) wherein M² is any of the following M^(2a) to M²¹:

 formula (V) is

 wherein n represents 1 or 2; and R²¹ and R³¹ each independently represents a hydrogen atom, an amino group, a C1-C6 alkyl group, an amino-C1-C6 alkyl group, or a C1-C6 alkylamino group; and Y^(a) and Y^(b) are


2. A compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein in the formula (I), Q represents an oxygen atom.
 3. A compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein in the formula (I), Q represents R^(a)N, wherein R^(a) represents a hydrogen atom or a C₁-C₆ alkyl group.
 4. A compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein in the formula (I), G is represented by the following formula (IV):

wherein U represents a nitrogen atom or CH; R⁷ represents a hydrogen atom or a C1-C6 alkyl group; and R⁸ represents a hydrogen atom, a C1-C6 alkyl group, or a halogen atom.
 5. A compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein in the formula (I), G is any of the following G^(a) to G^(e):


6. A compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein in the formula (I), Y⁴ represents —O-M², wherein M² is any of the following M^(2a) to M²¹:


7. A compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein in the formula (I), Y⁴ is represented by the following formula (V):

wherein n represents 1 or 2; and R²¹ and R³¹ each independently represents a hydrogen atom, an amino group, a C1-C6 alkyl group, an amino-C1-C6 alkyl group, or a C1-C6 alkylamino group.
 8. A compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein in the formula (I), Y⁴ is the following Y^(a) or Y^(b):


9. A pharmaceutical composition comprising a compound according to claim 1 or a pharmacologically acceptable salt thereof, as an active ingredient.
 10. A method for inhibiting proliferation of a cancer cell having a detectable increase in the expression level of ROS1 gene, comprising administering a compound according to claim 1 or a pharmacologically acceptable salt thereof.
 11. A method for inhibiting proliferation of a cancer cell having a detectable increase in the expression level of NTRK gene, comprising a compound according to claim 1 or a pharmacologically acceptable salt thereof.
 12. A method for inhibiting proliferation of a cancer cell having a detectable expression of ROS1 fusion gene, comprising administering a compound according to claim 1 or a pharmacologically acceptable salt thereof.
 13. A method for inhibiting proliferation of a cancer cell having a detectable expression of NTRK fusion gene, comprising administering a compound according to claim 1 or a pharmacologically acceptable salt thereof.
 14. A method for inhibiting proliferation of a cancer cell by the inhibition of ROS1 kinase enzyme activity, comprising administering a compound according to claim 1 or a pharmacologically acceptable salt thereof.
 15. A method for inhibiting proliferation of a cancer cell by the inhibition of NTRK kinase enzyme activity, comprising a compound according to claim 1 or a pharmacologically acceptable salt thereof.
 16. A method for inhibiting ROS1 kinase enzyme activity in a subject, comprising administering a compound according to claim 1 or a pharmacologically acceptable salt thereof.
 17. A method for inhibiting NTRK kinase enzyme activity in a subject, comprising administering a compound according to claim 1 or a pharmacologically acceptable salt thereof. 